Prostaglandins E and anti ulcers containing same

ABSTRACT

The novel 13, 14-dihydro-15-keto prostaglandins E of the invention have remarkable preventive effects against ulcers. Further, the novel 13,14-dihydro-15-ketoprostaglandins E of the invention have an advatage that they have none of side effects which prostaglandin E intrinsically has, or can remarakably reduce such effects of the prostaglandin E. 
     Therefore, the novel 13, 14-dihydro-15-keto prostaglandins E of the invention are effective for animal and human use for treatment and prevention of ulcers, such as duodenal ulcer and gastric ulcer.

This is a divisional of application Ser. No. 07/700,895 filed May 13,1991, now U.S. Pat. No. 5,166,174, which is a continuation ofapplication Ser. No. 07/406,830 filed Sep. 12, 1989, abandoned, which isa continuation-in-part of application Ser. No. 07/149,445 filed Jan. 28,1988, abandoned.

BACKGROUND OF THE INVENTION

The present invention relates to a novel type of prostaglandin E andulcer preventive agents containing the same.

Prostaglandin is a generic term for various prostanoic acids and isclassified into various groups, such as E, F, A, B, C, D, and H,according to the manner in which keto and/or hydroxyl groups areintroduced in five- membered ring portions. Prostaglandins willstimulate the uterine muscle and, in addition, they have variousphysiological and pharmacological actions, such as vasodilation,inhibition of platelet aggregation, and inflammatory action.

Prostaglandin E (hereinafter referred to as PGE), as a substance with afive-membered ring structure, has a group represented by: ##STR1##Broadly, there are known two types of PGE, namely, PGE₁ in which thecarbon-carbon bond at the 5- and 6-positions (C₅ -C₆ bond) is a singlebond: ##STR2## and PGE₂ in which the C₅ -C₆ bond is a double bond:##STR3## PGE₂, for example, is known as having antiulcer activity on onehand, but on the other hand it has such actions as uterine contraction,intestine contraction, and vasodilation; further it is recognized ashaving side effects, such as severe alvine flux. Therefore, it isunsuitable or impossible to use PGE₂ as antiulcers.

Whilst, it has been recognized that in human or animal metabolites thereare present free substances similar to prostaglandin E in which C₁₃ -C₁₄bond is saturated and in which the carbon at the 15-position forms acarbonyl group. These substances, or species of 13,14-dihydro-15-ketoprostaglandin E are: ##STR4## These corresponds to PGE₁, PGE₂, and6-keto PGE₁ respectively, and they are known as substances which arenaturally metabolically produced in vivo through enzymic metabolicreaction. These species of 13, 14-dihydro-15-keto PGE have been reportedas physiologically and pharmacologically inactive metabolic productswhich exhibit little of the various physiological activities of PGE(Acta Physiologica Scandinavica, Vol 66, p. 509˜, 1966), and has beenregarded as such. Therefore, little has been expected of thepharmacological effect of these metabolic products and compounds similarto them.

SUMMARY OF THE INVENTION

While evaluating the pharmacological activities of derivatives of theaforesaid metabolic products, the present inventor found that thederivatives, such as esters salts, one having a protective group on thecarboxyl group as well as one having free carboxyl group, one havingsubstituent groups at the 16-, 17-, 19-, and/or 20-positions, one inwhich the carbon at the 11- position has a methyl group or ahydroxymethyl group, and one having an alkoxy group at the terminal of aω chain, exhibited antiulcer activities, and that they showed no traceor a significantly reduced degree of such central and peripheralphysiological effects as were simultaneously appeared as a side effectand were inherent to known or common PGE which had been recognized ashaving antiulcer activities.

BRIEF DESCRIPTION OF DRAWING

FIG. 1-57 show n.m.r. spectra of the prostagrandins obtained in thepresent invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to 13,14-dihydro-15-keto prostaglandins Erepresented by the general formula: ##STR5## (in which X represents:##STR6## R₁ represents: hydrogen atom, physiologically acceptable salts,physiologically acceptable protective group C₁ -C₄ alkyl, benzyl,hydroxyalkyl, or alkoxyalkyl group;

R₂ represents: hydrogen atom or a methyl group;

R₃ represents: a hydroxyl, methyl, or hydroxymethyl group;

R₄ and R₅, each represents: hydrogen atom, or a methyl, hydroxyl group,or halogen atom (provided that R₄ and R₅ may be identical with ordifferent from each other); and

R₆ represents: C₁ -C₉ alkyl group which may have a branch or a doublebond, or C₁ -C₉ alkyl group having an alkoxy-substituent group,

in which C₂ -C₃ bond may be a double bond)

and antiulcers containing the same.

In the general formula (I), (X)- has any of the above shown structures.

A compound where -(X)- is ##STR7## is a prostaglandin belonging to thePGE₁ group, and a compound where -(X)- is ##STR8## is a prostaglandin tothe PGE₂. Therefore, a compound where -(X)- is ##STR9## is aprostaglandin to the 6-keto PGE₁. ##STR10## is a prostaglandins Ebelonging to 5,6-dehydro-PGE₂.

R₁ in the general formula (I) represents hydrogen atom an alkyl, benzyl,hydroxyalkyl, alkoxyalkyl group having 1-4 carbon atoms, aphysiologically acceptable salt residue, or a physiologically acceptableprotective group.

The alkyl group may be a cycloalkyl group, e.g., a cyclopropyl group, acyclopentyl group, or an alkyl group having a side chain or a doublebond structure, such as, for example, isopropyl group, tert-butyl group,or allyl group. Preferably, however, it is a straight chain saturatedalkyl group, or more specifically a methyl or ethyl group. Examples ofthe hydroxyalkyl group are hydroxyethyl and hydroxyisopropyl groups. Or,it may be an alkoxyalkyl group, such as methoxyethyl group oralkoxyalkyl group.

R₂ represents hydrogen or a methyl group, in which the carbons at the 2-and 3-positions may have a double bond.

The carboxyl group may be free, a salt residue, or a protective group.As the salt may be a physiologically acceptable salt, for example,alkaline metal salt such as sodium salt, potassium salt and the like;alkaline earth metal salt such as calcium, magnesium salt; ammoniumsalt; a physiologically acceptable amine salt such as salt ofmethylamine, dimethylamin, cyclopentylamine, benzylamine, pyperidine,monoethanolamine, diethanolamine, monomethylmonoethanolamine,tromethamine, lysine, tetraalkylammonium and the like. The protectivegroup may include alkylsilicon such as trimethylsilicon, triethylsiliconand the like; tetrahydroxypyran and the like.

R₃ represents a hydroxyl, methyl, or ethyl group, in which the stericconfiguration relating to the carbon at the 11-position may take theform of α, β, or a mixture thereof. Especially, one in which such stericconfiguration takes the α-position.

R₄ and R₅ are independently hydrogen, methyl or hydroxyl groups, orhalogens. R₄ and R₅ may be identical or different, but preferably atleast one of them is a methyl group or a halogen, or more particularlyfluorine atom.

R₆ is a saturated or unsaturated C₁ ˜C₉ alkyl group, or a C₁ ˜C₉ alkylgroup having an alkoxy-substituent group. For the alkyl group, onehaving C₄ ˜C₉ is particularly preferred. For such C₄ ˜C₉ alkyl group, astraight-chain alkyl group or an alkyl group having one methyl groupbranch is particularly preferred. In the alkyl group having an alkoxysubstituent, the alkoxy group is preferably methoxy or ethoxy, and forthe alkyl group, one having C₂ ˜C₆ is suitable.

The prostaglandin Es of the present invention includes isomers of theaforementioned compounds. Examples of these isomers include tautomericisomer between the hydroxyl group at 11-position and the carbonyl groupof 15-position, i.e. a hemiacetal. Such a tautomeric isomer is easilyformed in a compound having an electron attractive group such as afluorine atom.

Typical examples of the compounds according to the invention are:

13,14-dihydro-15-keto-PGE₂ alkyl ester;

13,14-dihydro-15-keto-PGE₂ cycloalkyl ester;

13,14-dihydro-15-keto-PGE₂ hydroxy alkyl ester;

13,14-dihydro-15-keto-PGE₂ benzyl ester;

13,14-dihydro-15-keto-PGE₁ alkyl ester;

13,14-dihydro-6,15-diketo-PGE₁ alkyl ester;

13,14-dihydro-15-keto-18-methoxy-19, 20-dinor-PGE₂ or alkylester;

13,14-dihydro-15-keto-18-methoxy-PGE₂ or alkylester;

13,14-dihydro-15-keto-Δ² -PGE₂ or alkyl ester;

13,14-dihydro-15-keto-20-methoxy-Δ² -PGE₂ or alkyl ester;

13,14-dihydro-15-keto-3R,S-methyl-PGE₂ or alkyl ester;

13,14-dihydro-15-keto-3R,S-methyl-20-methoxy-PGE₂ or alkyl ester;

13, 14-dihydro-15-keto-11-dehydroxy-11R-methyl-PGE.sub. 2 or alkylester;

13,14-dihydro-15-keto-16R,S-fluoro-11-dehydroxy-11R-methyl-PGE₂ or alkylester;

13,14-dihydro-15-keto-16R,S-hydroxy-PGE₂ or alkyl ester;

13,14-dihydro-15-keto-16R,S-fluoro-PGE₂ or alkyl ester;

13,14-dihydro-15-keto-16R,S-methyl-PGE₂ or alkyl ester;

13,14-dihydro-15-keto-16,16-dimethyl-PGE₂ or alkyl ester;

13,14-dihydro-15-keto-16,16-dimethyl-20-methoxy-PGE₂ or alkyl ester;

13,14-dihydro-15-keto-17S-methyl-PGE₂ or alkyl ester;

13,14-dihydro-15-keto-19-methy-PGE₂ or alkyl ester;

13,14-dihydro-15-keto-20-isopropropylidene PGE₂ or alkyl ester;

13,14-dihydro-15-keto-20-ethyl-PGE₂ or alkyl ester;

13,14-dihydro-15-keto-20-ethyl-11-dehydroxy-11R-methyl-PGE.sub. 2 oralkyl ester;

13,14-dihydro-15-keto-20-n-propyl-PGE₂ or alkyl ester;

13,14-dihydro-15-keto-20-ethyl-PGE₁ or alkyl ester;

13,14-dihydro-6,15-diketo-16R,S-fluoro-PGE₁ or alkyl ester;

13,14-dihydro-6,15-diketo-16R,S-fluoro-11-dehydroxy-11R-methyl-PGE₁ oralkyl ester;

13,14-dihydro-6,15-diketo-16R,S-methyl-PGE₁ or alkyl ester;

13,14-dihydro-6,15-diketo-16,16-dimethyl-PGE₁ or alkyl ester;

13,14-dihydro-6,15-diketo-19-methyl-PGE₁ or alkyl ester;

13,14-dihydro-6,15-diketo-20-methyl-PGE₁ or alkyl ester;

13,14-dihydro-6,15-diketo-11-dehydroxy-11R-methyl-PGE₁ or alkyl ester;and

13, 14-dihydro-6,15-diketo-11-dehydroxy-11R-hydroxymethyl PGE₁ alkylester.

13,14-dihydro-15-keto-20-methyl-PGE₁ or alkyl ester;

13,14-dihydro-15-keto-Δ² -PGE₁ or alkyl ester

13,14-dihydro-15-keto-16R,S-fluoro-20-methyl-PGE₂ or alkyl ester,

13,14-dihydro-15-keto-16,16-difluoro-PGE₂ or alkyl ester,

13,14-dihydro-15-keto-5,6-dehydro-20-methoxy-PGE₂ or alkyl ester.

The prostaglandins E of the present invention can be synthesized in suchway as shown illustrated in examples and the accompanying synthesischarts (I)˜(XXI). That is, a commercially available (-) or (±) Coreylactone (1) may be used as the starting material, and thencollins-oxidized to give an aldehyde (2); the aldehyde (2) may bereacted with dimethyl (2-oxoalkyl) phosphonate to give an α,β-unsaturated ketone (3), which is then reducted. The resultingunsaturated ketone (4) is protected with respect to its carbonyl group.A hydroxyl group after protective group, p-phenylbenzoate being removedis protected with THP. After lactone (7) is reduced to lactol (8), an αchain is introduced by Wittig reaction.

The PGE₂ in which - (X) - is ##STR11## can be obtained by reducing thelactone (7) to lactol (8), then subjecting the lactol (8) to reactionwith (4-carboxybutyl) triphenylphosphonium bromide.

The PGE₁ in which - (X)- is ##STR12## can be obtained through reductionof the PGE₂.

The 6-keto PGE₁ in which - (X)- is ##STR13## can be obtained by addingbromine or iodine atom on C₅ -C₆ double bond of ##STR14## usingN-bromosuccinimide or iodine atom, and simultaneously cyclizing the C₆-carbon and the hydroxyl group at the 9-position to give a bromide or aiodide, and then the bromide or iodide is treated with DBU to ketonizethe carbon at the 6-position.

5,6-Dehydro-PGE₂ s in which (X) is: ##STR15## may be prepared bytreating copper enolate which can be prepared by adding amonoalkyl-copper complex or a dialkylcopper complex of following formulaon 1,4-position of 4R-t-butyldimethylsilyloxy-2-cyclopentene-1-on (167):##STR16## with 6-carboalkoxy-1-iodo-2-hexine or its derivatives.

The compound in which R₃ is a methyl group can be obtained by Jones-oxidizing the hydroxyl group at the 9-position in 11-tosylate to form anPGA-type, then subjecting it to the action of a dimethyl copper complex.Alternatively, the compound can be synthesized by protecting thecarbonyl group of the saturated ketone (4) obtained by reduction of theunsaturated ketone (3), turning into tosylate the alcohol obtained afterrelease of P-phenylbenzoyl group, treating the tosylate with DBU,turning the resulting unsaturated lactone into lactol, introducing anα-chain into the lactol through Wittig reaction, oxidizing the resultingalcohol (9-position) to form an PGA-type, to which a dimethyl coppercomplex is reacted, then introducing a methyl group into the11-position.

The compound in which R₃ is hydroxymethyl group can be obtained byapplying benzophenone as a photosensitizer to the A-type prostaglandin(PGA) obtained in manner as above described, then adding methanol.

For the synthesis of the PGE in which either R₄ or R₅ is a group otherthan hydrogen atom, and of the PGE in which R₆ is other than n-butyl,the compound used in obtaining the α, β-unsaturated ketone (3), namely,dimethyl (2-oxoalkyl) phosphonate should be correspondingly replaced byother suitable compound. For example, where R₄ is fluorine atom, R₆ isn-butyl, and R₅ is hydrogen atom, dimethyl (3-fluoro-2-oxopeptyl)phosphonate may be used. Where R₄ and R₅ are hydrogen atom, and R₆ is anisopentyl group, dimethyl (6-methyl-2-oxoheptyl) phosphonate may beused.

The synthesis of the compounds of the invention is not limited to theforegoing. For protection of individual functional groups and foroxidation-reduction, suitable procedures may be applied as required.

The prostaglandins E of the present invention may be used as medicinesfor animal and human. Usually, they are used systemically or locally invarious ways, such as oral administration, intravenous injection, andsubcutaneous injection. The dosage varies according to the subject foradministration, animal or human, age, weight, symptoms, efficacy oftreatment, method of administration, and time of treatment.

Where the compounds of the invention are used in the form of solidcompositions for oral administration, they include tablets, powder, andgranules. In such solid composition, one or more active substances aremixed with at least one kind of inactive diluent, for example, lactose,mannitol, grape sugar, hydroxypropyl cellulose, crystallite cellulose,starch, polycinyl pyrrolidone, or magnesium metasilicoaluminate. Suchcomposition may, according to the conventional procedure, contain someadditive other than said inactive diluent, e.g., lubricant, such asmagnesium stearate, decomposer, such as calcium fibrogluconate,etherified cyclodextrin, such as a, α, β- or γ-cyclodextrin,dimethyl-α-, dimethyl-β-, or hydroxypropyl-β-cyclodextrin, branchedcyclodextrin, such as glucosyl-, or maltosylcyclodextrin, or stabilizer,such as formylated cyclodextrin, sulfur-containing cyclodextrin,misoprotol, or phospholipid. The aforesaid cyclodextrins may provideincreased stability. The stability may be improve by forming liposomewith a phospholipid.

Tablets or pills may be coated or covered with a gastrically solublematerial, such as refined sugar, gelatin, hydroxypropyl cellulose, orhydroxypropyl methyl cellulose phthalate, or a film of such matereial inone or more layers. Also, they may be encapsulized with an absorbablematerial, such as gelatin.

In the form of liquid compositions for oral administration, thecompounds of the invention include medically allowable emulsions,solutions, suspensions, syrups, and elixers. They may contain inactivediluents conventionally used, such as, for example, refined water,ethanol, and coconut oil. In addition to such inactive diluent, thecompositions may contain wetting agents, auxiliary agents, such assuspensions, edulcorants, flavors, aromatics, and preservatives. Theliquid compositions may be encapsulated as such in soft capsules and thelike.

Other forms of compositions for oral administration include spraysprepared per se according to the usual known procedures which maycontain one or more kinds of active substances.

The compounds of the invention in the form of injections for non-oraladministration include sterile aqueous and non-aqueous solvents,suspensions, emulsions, and detergents.

The aqueous solutions and suspensions include, for example, distilledwater and physiologic salt solution. The non- aqueous solutions andsuspensions include, for example, vegetable oils, such as polyethyleneglycol and olive oil, alcohols, such as ethanol, and Polysorbate. Suchcomposition may contain auxiliaries, such as presevatives, wettingagents, emulsions, and dispersions. These compositions are sterilized bybeing passed through bacteria retaining filters or by incorporation ofbactericides, or by light irradiation. It is also possible to firstprepare a germ-free solid composition and dissolve same in a germ-freeinjection solvent before using it as an injection.

EXAMPLE 1 1) Preparation of Dimethyl(3R,S-Fluoro-z-oxoheptyl)phosphonate ##STR17##

1 - 1 Methyl 2-R,S-Fluorocaproate:

Methyl 2R,S-bromocaproate (40 g) was added to anhydrous potassiumfluoride (23 g) in acetoamide (23 g) kept at 105° C. The mixture wasvigorously stirred at 105° C. for 6h. A crude product obtained after theusual work-up, was distilled under reduced pressure. Yield 20 g (71%),b.p. 66° C./20 mmHg.

1 - 2 Dimethyl (3R,S-Fluoro-2-oxoheptyl) phosphonate:

Dimethyl methylphosphonate (8.38 g) was dissolved in dry THF (200 ml),and the resulting solution was cooled to -78° C. n-Butyl lithium (1.6-M,42 ml) was added dropwise to the solution, and 10 min later 10 ml of theTHF solution of methyl 2R, S-fluorocaproate (20 g) was added dropwise.After the addition, the reaction solution was stirred at -78° C. for 45min, and then at room temperature for 45 min. A crude product obtainedafter the usual work-up was chromatographed (hexane: ethyl acetate=1:1).Yield 5.04 g (62%).

2) Preparation of Dimethyl (3R,S-Methyl-2-oxoheptyl)phosphonate##STR18##

2 - 1 Methyl 2R,S-Methylcaproate:

A THF (50 ml) solution of dissopropylamine (12.9 ml) was cooled to -78°C. and n-BuLi (1.6-M, 57,6 ml) was added dropwise over 1.5 h(preparation of LDA). A solution of methyl caproate (10 g) in THE (50ml) was added dropwise to the prepared LDA over 50 min. After stirringfor 2 h, a solution of methyl iodide (6.2 ml) in THF (20 ml) was addeddropwise over 40 min. The reaction solution was stirred at -78° C. for 1h, and then at room temperature overnight.

After the usual work-up, the resulting residue was distilled underreduced pressure, and thus 3.15 g of methyl 2R,S-methylcaproate (b.p.44° C./10 mmHg) was obtained.

2 - 2 Dimethyl (3-Methyl-2-oxoheptyl)phosphonate:

To a THF (120 ml) solution of dimethyl methylphosphonate (5.04 g) at-60° C. was added dropwise n-BuLi (1.6-M, 25.4 ml), and the mixture wasstirred for 30 min. A THF (50 ml) solution of methyl.2R,S-methylcaproate (3.15 g) was added dropwise. The mixture was stirredat -60° C. for 1 h, then at room temperature for 1.5 h, and thereafteracetic acid (2 ml) was added at 0° C. A crude product obtained after theusual work-up was chromatographed (hexane: ethyl acetate=1:5). Yeild:2,85 g (58%).

3) Preparation of Dimethyl (6-Methyl-2-oxoheptyl)phosphonate ##STR19##

3 - 1 Methyl 5-methylcaproate:

Sodium ethoxide was prepared from sodium metal (9.1 g) and freshlydistilled absolute ethanol (250 ml). Diethyl malonate (63.5 g) was addedto sodium ethoxide in ethanol, and the mixture was stirred at 60°-70° C.for 50 min. Isoamyl bromide (60 g) was added, and the reaction mixturewas heated under reflux overnight. After the usual work-up, theresulting crude product was distilled under reduced pressure to givediethyl isoamylmalonate. Yield: 71.7 g (78%).

Diethyl isoamylmalonate (71.7 g) was added to a 50% aqueous solution ofsodium hydroxide (60 ml), and the mixture was heated under reflux for 6h. After cooling, the mixture was extracted with ether; the water layerwas acidified with hydrochloric acid and, after saturation with sodiumchloride, was extracted with ether. The extracts from the acidic aqueouslayer were concentrated under reduced pressure to give isoamylmalonicacid. The obtained dicaboxylic acid was heated at 180° C. for 2 h. Afterdistillation under reduced pressure, 5-mehyl-caproic acid was obtained.Yield: 30 g (75%), b.p. 107°-108° C./11 mmHg.

The 5-methyl-caproic acid (30 g) was treated with methanol (600 ml) andsulfuric acid (3 ml), and thus methyl 5-methylcaproate was obtained.Yield: 27 g (81%).

3 - 2 Dimethyl (6-Methyl-2-oxoheptyl)phosphonate:

Dimethyl (6-methyl-2-oxoheptyl)phosphonate was prepared from methyl5-methylcaproate and dimethyl methylphosphonate according to the knownmethod.

4) Preparation of Dimethyl(3,3-Dimethyl-7-methoxy-2-oxoheptyl)phosphonate ##STR20##

4 - 1 Methyl 2,2-Dimethyl-6-methoxy caproate:

1,4-Butanediol (50 g) was treated with sodium hydride (NaH) (60%, 26,6g) and methyl iodide (250 g) in THF (150 ml) to give4-methoxy-1-butanol. Yield: 21.8 g (38%), b.p. 135/760 mmHg.

4-Methoxyl-1-butanol (8.49 g) was treated with p-toluenesulfonylchloride and 4-dimethylaminopyridine in methylene chloride (150 ml) togive 4-methoxy-butyl-1-tosylate. Yield: 16.1 g (77%).

4-Methoxy-butyl-1-tosylate (16.1 g), together with NaI (18.7 g), wasagitated in acetone (80 ml) at room temperature for 3 h to give1-iodo-4-methoxy-butane (9.05 g, 68%).

To N-isopropylcyclohexylamine (5.96 ml) in THF (30 ml) was addeddropwise n-BuLi (1,6-M, 22.7 ml) at -78° C., and the mixture was stirredfor 30 min, to which a THF (5 ml) solution of methyl isobutyrate (3.43g) was added, and stirred at -78° C. for 45 min. Then, a HMPA (6.3 ml)solution of 1-iodo-4-methoxy-butane (9.05 g) was added to the mixture,and stirred at room temperature for 1 h to give methyl2,2-dimethyl-6-methoxycaproate (4.81 g, 85%) after usual work-up.

4 - 2 Dimethyl (3,3-Dimethyl-7-methoxy-2-oxoheptyl)phosphonate:

Prepared from methyl 2,2-dimethyl-6-methoxycaproate and dimethylmethylphosphonate according to the known method.

5) Preparation of Dimethyl(3-(2-Tetrahydropyranyl)oxy-2-oxoheptyl)phosphonate ##STR21##

5 - 1 Methyl 2-(2-Tetrahydropyranyl)oxycaproate:

A tetrahydropyranyl ether was prepared from commercially availablemethyl 2R,S-hydroxycaproate according to the usual method. (Yield 71%).

5 - 2 Dimethyl (3-(2-Tetrahydropyranyl)oxy-2-oxoheplyl)phosphonate:

Prepared from methyl 2-(2-tetrahydropyranyl) oxycaproate and dimethylmethylphosphonate according to the known method. (Yield 48%).

6) Preparation of Dimethyl(4S-methyl-2-oxoheptyl)phosphonate ##STR22##

6 - 1 Ethyl 3S-Methyl-caproate:

Sodium ethoxide was prepared from sodium metal (7.61 g) and absoluteethanol (200 ml). Diethyl malonate (50.3 ml) was added dropwise to theethanol containing sodium ethoxide. After heating to 80° C.,2-bromopentane (50 g) was added and the mixture was reflued for 24 h.Diethyl (2-pentyl)malonate (62.7 g) was obtained after the usualwork-up. Diethyl (2-pentyl)malonate was added to a 50% potassiumhydroxide solution and the mixture was heated for 3 h whilewater/ethanol being distilled off. After cooling, the solution wasacidified with concentrated hydrochloric acid. Then, the solution wasextracted with ethyl acetate. The extract was concentrated under reducedpressure, and the resulting product was heated to 180° C. until bubblingceased. After distillation, colorless 3R,S-methy-caproic acid wasobtained. Yield: 27.7 g (35%), b.p. 200° C./760 mmHg.

3R,S-Methyl-caproic acid was dissolved in ehanol (160 ml) andcinchonidine (64 g) was added and dissolved under heating.

The solution was concentrated under reduced pressure, and the resultingsalt was recrystallized from 60% methanol six times to give needlecrystals. Yield: 14.4 g, (α)_(D) ⁻ =-3.3 (C=13.6 (benzene) literaturevalue -3.1)

3S-Methyl-caproic acid (3.94 g) was converted to the corresponding ethylester with using ethanol and catalytic amount of sulfuric acid. Yield:4.04 g (84%).

6 - 2 Dimethyl(4S-Methyl-2-oxoheptyl)phosphonate:

This compound was prepared from ethyl 3S-methyl-caproate and dimethylmethylphosphonate according to the known method.

7) Preparation of Dimethyl (3,3-Dimethyl-2oxoheptyl)phosphonate##STR23##

7 - 1 Ethyl 2,2-Dimethyl-caproate:

To LDA prepared at -78° C. in the usual manner was added ethylisobutyrate (45 g) in THF, and stirred for 1 h. A dry HMPA solution ofbutyl iodide (107 g) was added, and the mixture was stirred at -78° C.for 1 h and then at room temperature for additional 1 h.

A crude product obtained after tile usual work-up was distilled. Yield:50 g (75%), b.p. 68° C./25 mmHg.

7 - 2 Dimethyl(3,3-Dimethyl-2-oxoheptyl) phosphonate:

Prepared from ethyl 2,2-dimethyl-caproate and dimethyl methylphosphonateaccording to the usual method.

8) Preparation of (3R,S-Methyl-4-carboxybutyl) triphenylphosphoniumbromide ##STR24##

In ether (300 ml), 3-methyl-1,5-pentanediol (23.3 g) was converted to5-acetoxy-3-methyl-1-pentanol with pyridine (16 ml) and acetyl chloride(14 ml) at 0° C. Yield: 18.4 g.

5-Acetoxy-3-methyl-l-pentanol was oxidized with Jones reagent in acetone(200 ml) at -20° C. to give 5-acetoxy-3R,S-methyl valeric acid. Yield:8.2 g (24%).

To 5-acetoxy-3R,S-methyl valeric acid (8.2 g) was added hydrobromic acid(40 ml) and concentrated sulfuric acid (10 ml), and the mixture wasagitated at 90° C. overnight. Thereafter, the solution was poured intoiced water. A crude product obtained after the usual work-up waschromatographed (ethyl acetate: hexane=1.5), and thus 8.0 g of5-bromo-3R,S-methyl valeric acid (87%) was obtained.

5-Bromo-3R,S-methyl valeric acid with triphenyl phosphine (21.5 g) wasreflued in acetonitrile (100 ml) for 2 days. The reaction solution waspoured into ether and the resulting precepitate was separated byfiltration. Thus, (3-R,S-methyl-4-carboxybutyl)triphenylphosphoniumbromide was obtained. Yield: 9.78 g (52%).

EXAMPLE 2 (SEE CHART I) Preparation of 13,14-Dihydro-6,15-diketo-PGE₁ethyl ester (15), R: Et

2 - 1 Preparation of1S-2-Oxa-3-oxo-6R-(3-oxo-1-trans-octenyl)-7R-(4-phenylbenzoyl)oxy-cis-bicychlo(3,3, 0) octane (3):

To the suspension of sodium hydride (NaH) (60%, 250 mg) in THF (40 ml)was added dropwise dimethyl(2-oxoheptyl)phosphonate, and the reactionsolution was stirred for 30 min. A THF solution (40 ml) of the aldehyde(2) previously prepared by Collins oxidization of (-)-Corey lactone (1)(2 g) was added. Reaction was maintained at room temperature overnight,and then acetic acid was added. After the usual work-up, anα,β-unsaturated ketone (3) was obtained. Yield: 1.95 g (50%).

2 - 2 Preparation of1S-2-Oxa-3-oxo-6R-(3,3-ethylenedioxyoctanyl)-7R-(4-phenylbenzoyl)oxy-cis-bicyclo(3,3,0) octane (5):

The unsaturated ketone (3) was hydrogenated in ethyl acetate (100 ml)with using 5% paradium-carbon (100 mg) and hydrogen to give thecorresponding saturated ketone (4).

The ketone (4) (1.95 g) was dissolved in toluene (150 ml), and ethyleneglycol and p-toluenesulfonic acid (catalytic amount) were added. Thesolution was heated under reflux overnight while water produced wasdistilled off. After the usual work-up, ketal (5) was obtained. Yield:1.8 g (84%).

2 - 3 Preparation of1S-2-Oxa-3-oxo-6R-(3,3-ethylenedioxy-1-octanyl)-7R-hydroxy-cis-bicyclo(3,3,0) octane (6):

The compound (5) (1.8 g) was dissolved in methanol (80 ml) and THF (20ml), and after addition of potassium carbonate (0.563 g), the solutionwas stirred at room temperature for 7 h. A crude product obtained by ausual manner was chromatographed (ethyl acetatehexane=1:3→1:1) to givealcohol (6). Yield: 0.95 g (82%).

2 - 4 Preparation of tetrahydropyranyl ether (7):

The compound (6) (0.95 g) was dissolved in dichloromethane (100 ml) andthen dihydropyran (0.76 g) and p-toluene sulfonate (catalytic amount)were added. The resulting solution was stirred overnight. After theusual work-up and purification, tetrahydropyranyl ether (7) wasobtained. Yield: 1.06 g (88%).

2 - 5 Preparation of lactol (8):

To the tetrahydropyranyl ether (7) (1.06 g) in dry toluene (30 ml) at-78° C. was added dropwise diisobutylaluminum hydride (DIBAL-H) (1.5M,2.3 ml) and stirred for 60 min. Lactol (8) was obtained after the usualwork-up.

2 - 6 Preparation of13,14-Dihydro-11-(2-tetrahydropyranyl)oxy-15,15-ethylenedioxy PGF₂α (9):

Sodium hydride (60%, 0.86 g), washed with pentane, was suspended in DMSO(50 ml), and stirred for 90 min at 60°˜70° C. After the reactionsolution was cooled to room temperature,(4-carboxybutyl)triphenylphosphonium bromide in DMSO was added, andagitated for 30 min, to which lactol (8) in DMSO (10 ml) was added.After stirred overnight, the reaction solution was poured intoice-water, made basic with addition of 20% sodium hydroxide solution,and extracted with ether. The aqueous layer was adjusted to pH 4˜5 with4N-hydrochloric acid and extracted with ethyl acetate. The ethyl acetatelayer was washed with water, then with saturated sodium chloridesolution, and was dried over magnesium sulfate. Thereafter, the solventwas distilled off. Ether was added and insolubles were separated byfiltration. The filtrate was concentrated under reduced pressure to givethe compound (9).

2 - 7 Esterification of the compound (9);

Preparation of the compound (10), R=Et:

The carboxylic acid (9) was dissolved in dry acetonitrile (50 ml) andthen DBU (0.48 g) and ethyl iodide (1.76 g) were added. The solution wasstirred at room temperature overnight. A crude product was obtainedafter the usual work-up, and was column-chromatographed (ethylacetate-hexane 1:3). Thus, 1.04 g of ethylester (10) was obtained.(Yield: 76% from (7))

2 - 8 Preparation of the compound (11):

The alcohol (10) (1.04 g) was dissolved in dry tetrahydrofuran (3.4 ml)and dry methylene chloride (26.4 ml), and after addition of NBS (0.364g) at 0° C., the reaction solution was stirred for 5 min. A crudeproduct was obtained after the usual work-up, and chromatographed (ethylacetate-hexane=1:3) to give the compound (11). Yield: 0.61 g (51%).

2 - 9 Preparation of13,14-Dihydro-15,15-ethylenedioxy-6-keto-11-(2-tetrahydropyranyl)oxy-PGF.sub.1αethyl ester (13):

The bromoether (11) (0.61 g) was dissolved in dry toluene (30 ml), andthen DBU (25 ml) was added. The solution was agitated at 40° C.overnight. After the end of the period, the solution was cooled with iceand 1N-hydrochloric acid was added to acidify the solution, and agitatedfor 10 minutes. Subsequently, the solution was extracted with ethylacetate. A crude product was obtained after the usual work-up, and thenchromatographed (ethyl acetate-hexane=1:3→1:1) to give the compound(13). Yield: 0.332 g (61%).

2 - 10 Preparation of13,14-Dihydro-15,15-ethylenedioxy-6-keto-11-(2-tetrapyranyl)oxy-PGE₁ethyl ester (14):

The alcohol (13) (0.332 g) was oxidized in acetone (20 ml) at -20° C.with Jones reagent (2.67M, 0.36 ml). A crude product obtained after theusual work-up was chromatographed (ethyl acetate-hexane=1:3) to give thecompound (14). Yield: 0.198 g (58%).

2 - 11 Preparation of 13,14-Dihydro-6,15-diketo-PGE₁ ethyl ester (15):

The tetrahydropyranyl ether (14) (0.198 g) was dissolved in a mixedsolvent (14 ml) of acetic acid: water: THF (4:2:1), and the solution wasstirred for 1 h at 45° C. Benzene was added, and the solvent was removedunder reduced pressure. The resulting crude product was chromatographed(ethyl acetate-hexane=1:3) to give 13,14-dihydro-6,15-diketo-PGE₁ ethylester (15). Yield: 0.098 g (65%).

The n. m. r. spectrum of 13,14-dihydro-6,15-diketo-PGE₁ ethyl ester (15)is shown in FIG. 1.

Mass (SIMS) m/z: 397 (M+H)⁺, 379 ((M+H)⁺ -18), 287, 157, 111, 99.

EXAMPLE 3 (SEE CHART I) Preparation of (±)13,14-Dihydro-6,15-diketo-PGE₁ ethyl ester (15), R: Et

Preparation of the title compound was carried out using (±)-Coreylactone (1) and a similar manner to the Example 1.

The n. m. r. spectrum of (±)-13,14-dihydro-6,15-diketo-PGE₁ ethyl ester(15) is shown in FIG. 2.

Mass (SIMS) m/z: 397 (M+H)⁺, 379 ((M+H)⁺ -18), 287, 157, 111, 99.

EXAMPLE 4 (SEE CHART I) Preparation of 13,14-Dihydro-6,15-diketo-PGE₁methyl ester (15), R: Me

Preparation of the title compound was carried out in the same way as inExamples 2 and 3, except that (-)-Corey lactone (1) was used, and thatthe carboxylic acid (9) was methylated with diazomethane to give thecompound (10) (R=CH₃).

The n. m. r. spectrum of the 13,14-dihydro- 6,15-diketo-PGE₁ methylester (15) is shown in FIG. 2.

Mass (SIMS) m/z: 405 (M+H)⁺, 383 ((M+H)⁺ -18), 365, 287, 143, 121, 111,99.

EXAMPLE 5 (SEE CHARTS I and II) Preparation of13,14-Dihydro-15-keto-3R,S-methyl-PGE₂ methyl ester (19)

Sodium hydride (60%, 1.72 g), washed with pentane, was suspended in dryDMSO, and the suspension was agitated for 45 min at 70° C. After thereaction solution was ice-cooled, a DMSO solution of(3R,S-methyl-4-carboxybutyl)triphenylphosphonium bromide was added. Thereaction was stood at room temperature. Then, a DMSO solution of lactol(8) produced from (-)-Corey lactone with the procedure shown in Examples2 to 4 was added, and agitated for 2 h. The resultant was diluted with amixed solvent of ether and ethyl acetate (1:1), and poured into 5%potassium carbonate solution. After vigorous stirring, separated organiclayer was extracted with aqueous potassium carbonate solution twice. Thecombined basic aqueous layers were acidified with hydrochloric acid at0° C., and then were extracted with ethyl acetate three times. Thecombined ethyl acetate layers were washed with sodium chloride solution,and then concentrated under reduce pressure. The residue thus obtainedwas dissolved in ether and insolubles were filtered off. The filtratewas partially concentrated and was treated with diazomethane. Aftersubseqent concentration, a crude product was obtained, and waschromatographed (ethyl acetate-hexane=2:5) to give a colorless oilysubstance (17) (2.15 g, 56%).

The alcoholic substance (17) (2.1 g) was oxidized in acetone (60 ml) at-30° C. with Jones reagent (2.67-M) (2.20 ml).

A residue obtained after the usual work-up was chromatographed (ethylacetate: hexane=1:3) to give a colorless oily substance (18) (1.64 g,77%).

The tetrahydropyranyl ether (18) (1.64 g) was dissolved into a mixedsolvent (50 ml) of acetic acid: water: THF (4:2:1), and agitated for 3 hat 45° C. The reaction solution was concentrated under reduced pressure,and the resulting crude product was chromatographed (ethyl acetate:benzene=4:5) to give a colorless oily substance,13,14-dihydro-15-keto-3R,S-methyl-PGE₂ methyl ester (19). Yield: 0.98 g(80%).

The n. m. r. spectrum of 13,14-dihydro-15-keto-3R,S-methyl-PGE₂ methylester (19) is shown in FIG. 3.

Mass (D I) m/z: 380 (M⁺), 362 (M⁺ - 18), 208, 109, 94, 81.

EXAMPLE 6 (SEE CHART III) Preparation of13,14-Dihydro-15-keto-16R,S-methyl-PGE₂ ethyl ester (29), R=Et

6 - 1 Preparation of1S-2-Oxa-3-oxo-6R-(4R,S-methyl-3-oxo-1-trans-octenyl)-7R-(4-phenyl)benzoyloxy-cis-bicyclo (3, 3, 0) octane (20):

Sodium hydride (60%, 0.228 g) was suspended in anhydrous THF (40 ml),and a THF (30 ml) solution of dimethyl(3R,S-methyl-2-oxoheptyl)phosphonate (1.4 g) was added with agitationfor 30 min. To the resultant was added a THF solution (30 ml) of thealdehyde (2) obtained after collins oxidation of (-)- Corey lactone. Thereaction was kept at room temperature for 2 h, and then acetic acid wasadded to neutralize the reaction. An α,β-unsaturated ketone (20) wasobtained after the usual work-up and the purification. Yield: 1.606 g(61%).

6 - 2 Preparation of1S-2-oxa-3-oxo-6R-(3,3-ethylenedioxy-4R,S-methyl-1-octanyl)-7R-(4-phenyl)benzoyloxy-cis-bicyclo (3, 3, 0) octane (22):

The α,β-unsaturated ketone (20) was hydrogenated in ethyl acetate with5% palladium-carbon (0.150 g), and hydrogen. The saturated ketone (21)thus obtained was dissolved in anhydrous benzene (150 ml), to whichp-toluenesulfonic acid (in catalytic amount) and ethylene glycol (10 ml)were added, and refluxed overnight while water was distilled off. Ketal(22) was obtained after the usual work-up. Yield: 1.538 g (87%).

6 - 3 Transesterification of the ketal (22): Synthesis of alcohol (23):

The ketal (22) (1.538 g) was dissolved in absolute methanol (100 ml),and K₂ CO₃ (0.503 g) was added, the reaction was stirred for 5 h.

The reaction solution was neutralized with addition of acetic acid.

A crude product obtained after the usual work-up was chromatographed(ethyl acetate: hexane=1:2) to give the alcohol (23). Yield: 0.8682 g(88%).

6 - 4 Preparation of Tetrahydropyranyl ether (24):

The compound (23) (0.8682 g) was dissolved in dry CH₂ Cl₂ (100 ml), anddihydropyran (5 ml) and p-toluenesulfonic acid (catalytic amount) wereadded. The reaction solution was stirred for 20 min. A crude productobtained after the usual work-up was chromatographed (hexane: ethylacetate=5:1) to give the tetrahydropyranyl ether (24). Yield: 1.040 g(94%).

6 - 5 Preparation of lactol (25):

The tetrahydropyranyl ether (24) was treated with DIBAL-H (1.5-M, 5 ml)in dry toluene (30 ml) at -78° C. to give the lactol (25). Yield: 1.030g.

6 - 6 Preparation of13,14-Dihydro-15,15-ethylenedioxy-16R,S-methyl-11-(2-tetrahydropyranyl)oxy-PGF₂α (26):

Sodium hydride (50%, 0.600 g) washed with dry ether was suspended inDMSO (8 ml), and the suspension was heated at 60° C. for 1 h withagitation. A DMSO (10 ml) solution of(4-carboxybutyl)triphenylphosphonium bromide (3.3 g) was added dropwise.Deep red ylide was obtained, to which the above lactol (25) in DMSO (8ml) was added. The reaction was kept overnight at room temperature withstirring, and then poured into an ice-water, the aqueous solution wasadjusted to pH 12 with 10% sodium hydroxide solution. The basic aqueoussolution was extracted with ethyl acetate. The aqueous layer wasadjusted to PH 6 with 1N hydrochloric acid at 0° C., and was extractedwith ethyl acetate, and the combined organic extract were washed withbrine. After drying, the extract was concentrated under reduced pressureto give the carboxylic acid (26). Yield: 1.299 g.

6 - 7 Preparation of ethyl ester (27), R=Et:

Esterification of the compound (26):

The carboxylic acid (26) (1.299 g) was dissolved in dry acetonitrile (50ml). To the solution were added ethyl iodide (0.6 g) and DBU (0.4750 g).The mixture was kept at 60° C. for 2 h. A crude product obtained afterthe usual, work-up, was chromatographed (hexane: ethyl acetate=2:1) togive 0.6226 g of the ethyl ester (27). (Yield: 48%, from (24)).

6 - 8 Preparation of ketone (28):

The ethyl ester (27) (0.6226 g) was oxidized with Jones reagent (2.67 -M, 0.45 ml) in acetone (40 ml) at -40° C.

A crude product obtained after the usual work-up was chromatographed(hexane-ethyl acetate=3:1). Yield: 0.3942 g (63%).

6 - 9 Preparation of 13,14-Dihydro-15-keto-16R,S-methyl-PGE₂ ethyl ester(29): The ketone (28) (0.3942 g) was dissolved in a mixted solvent (10ml) of acetic acid: water: THF (3:1:1), and the solution was kept at40,° C. for 4 h. A crude product obtained after the usual work-up waschromatographed (hexane-ethyl acetate=4:1) to give13,14-dihydro-15-keto-16R,S-methyl-PGE₂ ethyl ester (29). Yield: 0.1559g (53%).

The n. m. r. spectrum of the 13,14-Dihydro-15-keto,-16R,S-methyl-PGE₂ethyl ester (29) is shown in FIG. 4.

Mass (SIMS) m/z: 395 (M+H)⁺, 377 ((M+H)⁺ -18), 331, 203, 109, 85.

EXAMPLE 7 (SEE CHART III) Synthesis of13,14-Dihydro-15-keto-16R,S-methyl-PGE₂ methyl ester (29), R=Me

The title compound (29) was prepared in the same manner as in Example 6except-that the carboxylic acid (26) was methylated with diazomethane.

The n. m. r. spectrum of the 13,14-dihydro-15-keto-16R,S-methyl-PGE₂methyl ester (29) is shown in FIG. 5.

Mass (D I) m/z: 380 (M⁺), 362 ((M⁺ -18), 331, 249, 234, 222, 137, 109.

EXAMPLE 8 (SEE CHART IV) Synthesis of13,14-Dihydro-6,15-diketo-16R,S-methyl-PGE₁ ethyl ester (33), R=Et

8 - 1 Preparation of bromide (30) R=Et:

PGF₂ -ethyl ester derivative (27) (1.405 g) was dissolved in a mixtedsolvent (50 ml) of THF-CH₂ Cl₂ (2:5). To the solution was added aTHF-CH₂ Cl₂ (2:5; 20 ml) solution of NBS (0.5250 g) at 0° C., which wasagitated for 20 min. A crude product obtained after the usual work-upwas chromatographed (hexane: ethyl acetate=3:1) to give the bromide(30). Yield: 1.592 g (98%).

8 - 2 Preparation of13,14-Dihydro-15,15-ethylenedioxy-6-keto-16R,S-methyl-11-(2-tetrahydropyranyl)oxy-PGF₂αethyl ester (31):

The bromide (30) (1.592 g) was dissolved in toluene (4 ml) and DBU (3.5ml), and the solution was stirred at 50° C. overnight. After cooled, thesolution was diluted with ether, and washed with sodium hydrogensulfitesolution. A crude product obtained after the usual work-up waschromatographed (hexane: ethyl acetate=1.5:1) to give the compound (31).Yield: 1.031 g (72%).

8 - 3 Preparation of ketone (32):

The 6-keto-PGF derivative (31) (0.5012 g) was oxidized with Jonesreagent (2.67-M: 1.2 ml) in acetone (35 ml) at -25° C. A crude productobtained after the usual work-up was chromatographed (hexane: ethylacetate v=1:1) to give the ketone (32). Yield: 0.3907 g (78%).

8 - 4 Preparation of 13,14-Dihydro-6,15-diketo-16R,S-methyl-PGE₁ ethylester (33):

The 6-keto-PGF derivative (32) (0.3907 g) was dissolved in a mixedsolvent (24 ml) of acetic acid: water: THF (3:1:1) and the solution waskept at 50° C. for 3.5 h. After cooled, the solution was concentratedunder reduced pressure. The resulting crude product was chromatographed(hexane: ethyl acetate=1:1) to give13,14-dihydro-6,15-diketo-16R,S-methyl-PGE₁ ethyl ester (33). Yield:0.2100 g (71%).

The n. m. r. spctrum of 13,14-dihydro-6,15-diketo-16R,S-methyl-PGE₁ethyl ester (33) R; Et, is shown in FIG. 6.

Mass (SIMS) m/z: 411 (M+H)⁺, 393 ((M+H)⁺ -18), 375, 347, 301, 149, 130.

EXAMPLE 9 (SEE CHART IV)

Synthesis of 13,14-Dihydro-6,15-diketo-16R, S-methyl-PGE₁ methyl ester(33), R=Me:

The title compound (33) was prepared from the methyl ester (27)following the same manner as the preparation of13,14-dihydro-6,15-diketo-16R,S-methyl-PGE₁ ethyl ester (33).

The n. m. r. spctrum of the 13,14-dihydro-6,15-diketo-16R,S-methyl-PGE₁methyl ester (33) is shown in FIG. 7.

Mass (SIMS) m/z: 397 (M+H)⁺, 379 ((M+H)⁺ -18), 365, 347, 301, 143, 121,111.

EXAMPLE 10 (SEE CHART V) Preparation of13,14-Dihydro-15-keto-3R,S,16R,S-dimethyl-PGE₂ methyl ester (36)

10 - 1 Preparation of 13,14-Dihydro-15,15-ethylenedioxy-3R,S,16R,S-dimethyl-11-(2-tetrahydropyranyl)oxy-PGE₂α methyl ester(34):

Sodium hydride (60%, 0.4660 g), washed with dry ether, was suspended indry DMSO (8 ml), and the suspension was stirred at 60° C. for 1 h. ADMSO solution of (3R,S-methyl-4-carboxybutyl)triphenylphosphoniumbromide (2.66 g) was added to sodium methylsulfinyl carbonion to givedeep red ylide. After addition, the reaction solution was stirred for 15minutes. A DMSO solution (10 ml) of lactol (25) (0.8 g) was addeddropwise, and the mixture was agitated overnight. The reaction solutionwas poured in ice-water and adjusted to pH 12 with 10% sodium hydroxidesolution, and then extracted with ether. The aqueous layer was adjustedto pH 5-6 with 1-N hydrochrolic acid and then extracted with ether. Theorganic extract of the acidic aqueous solution was dried, andconcentrated under reduced pressure. The crude product thus obtained wasesterified with diazomethane and then was chromatographed to give13,14-dihydro-3R,S,16R,S-dimethyl-15,15-ethylenedioxy-11-(2-tetrahydropyranyl)oxy-PGE₂methyl ester (34). Yield: 0.7483 g.

10 - 2 Preparation of 13,14-Dihydro-15-keto-3R,S, 16R,S-dimethyl-PGE₂methyl ester (36):

According to the manner analogous to the Examples 2 to 9 with using thePGF₂ derivative (34), 13,14-dihydro- 15-keto-3R,S, 16R,S-dimethyl-PGE₂methyl ester (36) was produced.

The n. m. r. spectrum of13,14-dihydro-15-keto-3B,S,16R,S,S-dimethyl-PGE₂ methyl ester (36) isshown in FIG. 8.

Mass (SIMS) m/z: 395 (M+H)⁺, 377 ((M+H)⁺ -18), 345, 121, 109, 95.

EXAMPLE 11 (SEE CHART VI) Preparation of13,14-Dihydro-6,15-diketo-16R,S-fluoro-PGE₁ ethyl ester (50)

11 - 1 Preparation of 1S-2-Oxa-3-oxo-6R-(4R,S-fluoro-3-oxo-1-trans-octenyl)-7R-(4-phenylbenzoyl)oxy-cis-bicyclo (3,3, 0) octane (37):

Sodium hydride (60%, 1.70 g) was suspended in THF, and a THF solution ofdimethyl(3R,S-fluoro-2-oxoheptyl)phosphonate (4) (10.23 g) was added tothe suspension, and agitated at room temperature for 20 min. To themixture was added a THF solution of aldehyde (2) which was obtainedafter Collins-oxidation of the (-)-lactone (1) (15.00 g).

After 2 h agitation at room temperature, the reaction solution wasneutralized with acetic acid (15 ml). Thereafter, a residue obtainedafter the usual work-up was purified by column-chromatography (ethylacetate: hexane=1:2) to give a colorless oily enone (37) Yield: 10.45 g(53%).

11 - 2 Preparation of 1S-2-Oxa-3-oxo-6R-(4R,S-fluoro-3R,S-hydroxy-1-octyl)-7R-(4-phenylbenzoyl)oxy-cis-bicyclo (3,3, 0) octane (39):

The enone (37) (10.45 g) was hydrogenated with 5% palladium or carbon(1.0 g) and hydrogen in ethyl acetate (50 ml) to give ketone (38).Yield: 9.35 g (89%).

The ketone (38) (9.35 g) was reduced with sodium borohydride (1.15%) inabsolute methanol (200 ml) to give a colorless oily substance (39).Yield: 6.50 g (69%).

11 - 3 Preparation of1S-2-Oxa-3-oxo-6R-(4R,S-fluoro-3R,S-t-butyldimethylsilyloxy-1-octyl)-7R-hydroxy-cis-bicyclo(3,3, 0)octane (41): ##STR25##

The alcohol (39) (6.50 g) was converted with t-butyldimethylsilylchloride (6.27 g) and imidazole (5.67 g) in dry DMF (30 ml) to thecorresponding t-butyldimethylsilyl ether (40). Yield: 8.80 g (100%).##STR26##

The t-butyldimethylsilyl ether (40) (8.80 g) was dissolved in methanol(80 ml), and anhydrous potassium carbonate (2.09 g) was added to thesolution. The reaction was stirred for 4 h at room temperature. Acolorless oily alcohol (41) was obtained after the usual work-up, andpurification. Yield: 4.11 g (67%).

11 - 4 Preparation of13,14-Dihydro-16R,S-fluoro-15R,S-t-butyldimethylsilyloxy-11-(2-tetrahydropyranyl)oxy-PGF₂α(44): ##STR27##

The alcohol (41) (4.11 g) was dissolved in dry dichloromethane (50 ml),and dihydropyran (4.10 ml) and p-toluenesulufonic acid (catalyticamount) were added to the solution. The reaction solution was stirred atroom temperature for 10 min. The residue obtained after usual work-upwas chromatographed (ethyl acetate: hexane=1:4˜1:3) to give a colorlessoily tetrahydropyranyl ether (42). Yield 5.0δg (100%). ##STR28##

The tetrahydropyranyl ether (42) (5.08 g) was reduced with DIBAL-H(1.5M, 20 ml) in dry toluene (60 ml) at -78° C., and a colorless oilylactol (43) was obtained. ##STR29##

Ylide was prepared from (4-carboxybutyl) triphenylphosphonium bromide(18.51 g) according to the usual procedure, and to this ylide was addeda DMSO solution of the previously prepared lactol (43). The reactionsolution was stirred at room temparature for 2 h. The residue obtainedafter the usual work-up was dissolved in ether. After insoluble materialwas separated by filtration, the filtrate was concentrated under reducedpressure, and a crude carboxylic acid (44) was obtained. Yield: 8.0 g.

11 - 5 Preparation of13,14-Dihydro-16R,S-fluoro-15R,S-hydroxy-11-(2-tetrahydropyranyl)oxy-PGF.sub.2αethyl ester (46):

The crude carboxylic acid (44) (8.0 g) was dissolved in dry acetonitrile(40 ml), and DBU (3.0 ml) and ethyl iodide (6.0 ml) were added, andagitated at 60° C. for 60 min. The residue obtained after usual work-upwas chromatographed (with ethylacetate: hexane=1:4˜1:2) to give acolorless oily ester (45). Yield: 1.84 g.

The ester (45) (1.84 g) was dissolved in dry THF (30 ml), andtetrabutylammonium fluoride (1.0-M, 45 ml) was added. The reactionsolution was stirred at room temperature for 3.5 h. The reside obtainedafter the usual work-up was chromatographed (ethyl acetate:hexane=1:2˜1:3) to give a colorless oily alcohol (46). Yield: 1.34 g(90%).

11 - 6 Preparation of13,14-Dihydro-16R,S-fluoro-15R,S-hydroxy-6-keto-11-(2-tetrahydropyranyl)oxy-PGF₂ethyl ester (48):

The alcohol (46) (0.6254 g) was dissolved in dry dichloromethane (30 ml)and dry THF (3 ml), and N-bromosuccinimide (0.229 g) were added. Thereaction solution was stirred for 10 min. The residue obtained after theusual work-up was chromatographed (ethyl acetate: hexane=2:3) to give acolorless oily bromo-ether (47). Yield: 0.6837 g (94%).

The bromo-ether (47) (0.8243 g) was dissolved in dry toluene (20 ml) andDBU (2.20 ml). The mixture was stirred at 65° C. overnight. Afteraddition of water to the reaction solution, the mixture was acidifiedwith dilute hydrochloric acid under ice cooling, and was extracted withethyl acetate. The residue obtained after the usual work-up waschromatographed (ethyl acetate: hexane=1:1˜2:1) to give a colorless oily6-keto substance (48). Yield: 0.482 g (66%).

11 - 7 Preparation of 13,14-Dihydro-6,15-diketo-16R,S-fluoro-PGE₁ ethylester (50):

The dialcoholic substance (48) (0.230 g) was oxidized in acetone (20 ml)at -10° C. to -8° C. with Jones reagent (2.67M, 1.5 ml).

The residue obtained after the usual work-up was chromatographed (withethyl acetate: hexane=1:2) to give a colorless oily keto substance (49).Yield: 0.100 g (44%)

The tetrahydropyranyl ether (49) (0.200 g) was dissolved in a mixedsolvent (20 ml) of acetic acid: water: THF (4:2:1), and the solution wasstirred at 47° C. for 3 hours.

The reaction solution was concentrated under reduced pressure, and theresulting residue %las chromatographed (ethyl acetate: hexane=1:1) togive 13,14-dihydro-6,15-diketo-16R,S-fluoro-PGE₁ ethyl ester (50).Yield: 0.153 g (92%).

The n. m. r. spectrum of 13,14-dihydro-6,15-diketo-16R,S-fluoro-PGE₁ethyl ester (50) is shown in FIG. 9.

Mass (SIMS) m/z: 415 (M+H)⁺, 397 ((M+H)⁺ -18), 377, 351, 305, 157, 111.

EXAMPLE 12 (SEE CHART VII) Preparation of13,14-Dihydro-15-keto-16R,S-fluoro- 11R-dehydroxy-11R-methyl-PGE₂ ethylester (54)

12 - 1 Preparation of13,14-Dihydro-15R,S-t-butyldimethylsilyloxy-16R,S-fluoro-11-(2-tetrahydropyranyl)oxy-PGE₂ ethyl ester (51): ##STR30##

The alcohol (45) (0.506 g) was oxidized (2.67M) in acetone at -30° C.with Jones reagent. The crude product obtained after the usual work-upwas chromatographed (ethyl acetate: hexane=2:9) to give a ketonicsubstance (51). Yield: 0.380 g (75%).

12 - 2 Preparation of 13,14-Dihydro-16R,S-fluoro-15R,S-hydroxy-PGA₂ethyl ester (52):

The tetrahydropyranyl ether (51) was dissolved in 23 ml of a mixedsolvent of acetic acid and water (20:3), and the solution was stirred at70° C. The reactant was concentrated under reduced pressure, and thenwas chromatographed (ethyl acetate: hexane=1:3˜1:1) to give a colorlessoily enone (52). Yield: 0.078 g (32%).

12 - 3 Preparation of13,14-Dihydro-15-keto-16R,S-fluoro-11R-dehydroxy-11R-methyl-PGE₂ ethylester (54):

Cuprous iodide (0.318 g) was suspended in anhydrous ether (30ml), andmethyl lithium (15-M; 2.23 ml) was added dropwise to the suspension at-13° C. to give a clear solution, to which the enone (52) (0.080 g) inether (20 ml) was added. The reaction solution was stirred for 45 min.Then, acetic acid (0.84 ml) was added. The mixture was poured into anaqueous ammonium chloride, and extracted with ether.

The extract was washed, dried, and then concentrated under reducedpressure. The resulting crude product was chromatographed (ethylacetate: hexane=2:5) to give a colorless oily alcoholic substance (53).Yield: 0.075 g (90%).

The alcoholic substance (53) (0.136 g) was oxidized with Jones reagent(2.67M) in acetone (20 ml) at -10° C. to -8° C. A crude product obtainedafter the usual work-up was chromatographed (ethyl acetate: hexane=1:4)to give colorless oily13,14-dihydro-15-keto-16R,S-fluoro-11R-dehydroxy-11R-methyl-PGE₂ ethylester (54). Yield: 0.122 g (90%). ##STR31##

The n. m. r. spectrum of13,14-dihydro-15-keto-16R,S-fluoro-11R-dehydroxy-11R-methyl-PGE₂ ethylester (54) is shown in FIG. 10.

Mass (SIMS) m/z: 397 (M+H)⁺, 379 ((M+H)⁺ -18), 329, 301, 258, 237, 207,167, 132.

EXAMPLE 13 Preparation of 13,14-Ddihydro-15-keto-16R,S-fluoro-PGE₂ ethylester (56) ##STR32##

Diol (46) (chart VI) (0.501 g) was dissolved in acetone (35 mi) and wasoxidized with Jones reagent at -35° C. (2.67-M; 1 ml).

The crude product obtained after the usual work-up was chromatographedto give a tetrahydropyranyl ether (55). Yield: 0.347 g (70%). ##STR33##

The tetrahydropyranyl ether (55) (0.347 g) was dissolved in 25 ml of amixed solvent of acetic acid: THF: water (3:1:1), and the solution wasstirred at 40° C. for 12 h.

A crude product obtained after the usual work-up was chromatographed togive 13,14-dihydro-15-keto-16R,S-fluoro-PGE₂ ethyl ester (56). Yield:0.204 g (71%).

The n. m. r. spectrum of 13,14-dihydro-15-keto-16R,S-fluoro-PGE₂ ethylester (56) is shown in FIG. 11.

Mass (D I) m/z: 398 (M+H)⁺, 380 (M⁺ - 18), 226, 109, 95, 81.

EXAMPLE 14 Preparation of 13,14-Dihydro-6,15-diketo-16,16-dimethyl-PGE₁ethyl ester (57) ##STR34##

The title compound (57) was prepared following the procedure analogousto that in Example 2 to 13 with using (-)-Corey lactone (1) anddimethyl(3,3-dimethyl-2-oxoheptyl)phosphonate.

The n. m. r. spectrum of 13,14-dihydro-6,15-diketo-16,16-dimethyl-PGE₁ethyl ester (57) is shown in FIG. 12.

Mass (D I) m/z: 398 (M+H)⁺, 380 (M⁺ - 18), 226, 109, 95, 81.

EXAMPLE 15 Preparation of 13,14-Dihydro-15-keto-17S-methyl-PGE₂ ethylester (58) ##STR35##

The same procedure as in Examples 1 to 14 was followed using dimethyl(4S-methyl-2-oxoheptyl)phosphonate and (-)- Corey lactone (1), and thus13,14-Dihydro-15-keto-17S-methyl-PGE₂ ethyl ester (58) was synthesized.

The n. m. r. spectrum of 13,14-dihydro-15-keto-17S-methyl-PGE₂ ethylester (58) is shown in FIG. 13.

Mass (D I) m/z: 394 (M⁺), 376 (M⁺ - 18), 222, 109, 94.

EXAMPLE 16 (SEE CHART VIII) Preparation of13,14-Dihydro-15-keto-19-methyl-PGE₂ ethyl ester (60), R=Et:

Same procedure as in Examples 2 to 15 was followed using the unsaturatedketone (59) obtained from dimethyl (6-methyl-2-oxoheptyl)phosphonate and(-)-Corey lactone (1), and thus 13, 14-dihydro-15-keto-19-methyl-PGE₂ethyl ester (60) was synthesized.

The n. m. r. spectrum of 13,14-dihydro-15-keto-19-methyl-PGE₂ ethylester (60) is shown in FIG. 14.

Mass (D I) m/z: 394 (M⁺) 376 (M⁺ - 18), 331, 222, 109, 95, 94.

EXAMPLE 17 (SEE CHART VIII) Preparation of13,14-dihydro-15-keto-19-methyl-PGE₂ methyl ester (61), R=Me

Preparation was carried out using the unsaturated ketone (59) and thesame way as in Examples 2 to 16.

The n. m. r. spectrum of 13,14-dihydro-15-keto-19-methyl-PGE₂ methylester (61) is shown in FIG. 15.

Mass (D I) m/z: 380 (M⁺), 362 (M⁺ - 18), 331, 222, 109, 95, 94.

EXAMPLE 18 (SEE CHART VIII) Preparation of13,14-Dihydro-6,15-diketo-19-methyl-PGE₁ ethyl ester (62), R=Et

Preparation was carried out using the unsaturated ketone (59) and thesame way as in Examples 2 to 17.

The n. m. r. spectrum of 13,14-dihydro-6,15-diketo-19-methyl-PGE₁ ethylester (62) is shown in FIG. 16.

Mass (SIMS) m/z: 411 (M+M)⁺, 393 ((M+H)⁺ - 18), 323, 292, 291, 217, 201,109.

EXAMPLE 19 (SEE CHART VIII) Preparation of13,14-Dihydro-6,15-diketo-19-methyl-PGE₁ methyl ester (63), R=Me

Preparation was carried out using the unsaturated ketone (59) and thesame way as in Examples 2 to 18.

The n. m. r. spectrum of 13,14-dihydro-6,15-diketo-19-methyl-PGE₁ methylester (63) is shown in FIG. 17.

Mass (D I) m/z: 369 (M⁺), 378 ((M⁺ - 18), 265, 235, 143, 111.

EXAMPLE 20 Preparation of13,14-Dihydro-15-keto-16,16-dimethyl-20-methoxy-PGE₂ methyl ester (64)

The same procedure as in Examples 2 to 19 was followed using dimethyl(3,3-dimethyl-7-methoxy-2-oxoheptyl)phosphonate and (-)-Corey lactone(1), and thus 13,14-dihydro-15-keto-16,16-dimethyl-20-methoxy-PGE₂methyl ester (64) was prepared.

The n. m. r. spectrum of13,14-dihydro-15-keto-16,16-dimethyl-20-methoxy-PGE₂ methyl ester (64)is shown in FIG. 18.

Mass (E I) m/z: 424 (M⁺), 406 ((M⁺ - 18), 375, 266, 375, 266, 245, 217,129.

EXAMPLE 21 Preparation of 13,14-Dihydro-15-keto-16R,S-hydroxy-PGE₂ ethylester (65) ##STR36##

The same procedure as in Examples 2 to 20 was followed using (-)-Coreylactone (1) anddimethyl(3-(2-tetrahydropyranyl)oxy-2-oxoheptyl)phosphonate, and thus13,14-dihydro-15 keto-16R,S-hydroxy PGE₂ ethyl ester (65) wassynthesized.

The n. m. r. spectrum of 13,14-dihydro-15 keto-16R,S-hydroxy-PGE₂ ethylester (65) is shown in FIG. 19.

Mass (D I) m/z: 396 (M⁺), 378 ((M⁺ - 18), 333, 309, 96, 81.

EXAMPLE 22 (SEE CHART IX) Preparation of 13,14-Dihydro-15-keto-PGE₁ethyl ester(66), R: Et

22 - 1) Preparation of13,14-Dihydro-15,15-ethylenedioxy-11-(2-tetrahydropyranyloxy)-PGF₁.alpha.ethyl ester (64), R: Et

13,14-dihydro-15,15-ethylenedioxy-11-(2-tetrahydropyranyl)oxy-PGF₂.alpha.ethyl ester (10), R=Et, (3.56 g) was hydrogenated with platinum oxideand hydrogen in ethanol (150 ml). After the usual work-up, there wasobtained 3.50 g of13,14-dihydro-15,15-ethylenedioxy-11-(2-tetrahydropyranyl)oxy-PGF₂.alpha.ethyl ester (64).

22 - 2) Preparation of13,14-Dihydro-15,15-ethylenedioxy-11-(2-tetrapyranyl)oxy-PGE₁ ethylester (65):

13,14-dihydro-15,15-ethylenedioxy-11-(2-tetrahydropyranyl)oxy-PGF₁.alpha.ethyl ester (64) (3.25 g) was oxidized with Jones reagent (2.67- M; 3.2ml) in acetone (100 ml) at -300+ C. The crude product obtained after theusual work-up was chromatographed (hexane: ethyl acetate=5:2) to give13,14-dihydro-15,15-ethylenedioxy-11-(2-tetrahydropyranyl) oxy-PGE₁ethyl ester (65). Yield 2.72 g.

22 - 3) Preparation of 13,14-Dihydro-15-keto-PGE₁ ethyl ester (66):

13,14-Dihydro-15,15-ethylenedioxy-11-(2-tetrahydropyranyl)oxy-PGE₁ ethylester (65) (2.72 g) was dissolved in a mixed solvent (90 ml) of aceticacid: water: THF (4:2:1), and the solution was agitated for 3 h at40°˜45° C. The solvent was distilled off under reduced pressure, and theresulting crude product was chromatographed twice (hexane: ethylacetate=1:1, and ethyl acetate: benzene=1:1) to give13,14-dihydro-15-keto-PGE₁ ethyl ester (66).

The n. m. r. spectrum of 13,14-Dihydro-15-keto-PGE₁ ethyl ester (66) isshown in FIG. 20.

EXAMPLE 23 (SEE CHART IX) Preparation of 13, 14-Dihydro-15-keto-PGE₁methyl ester (66), R: Me

The same procedure as in Example 22 was followed using13,14-dihydro-15,15-ethylenedioxy-11-(2-tetrahydropyranyl)oxy-PGF₂.alpha.a methyl ester (10), the compound obtained from the carboxylic acid (9)with diazomethane, and thus 13,14-dihydro-15-keto-PGE₁ methyl ester (66)was synthesized.

The n. m. r. spectrum of 13,14-dihydro-15-keto-PGE₁ ethyl ester (66) isshown in FIG. 21.

EXAMPLE 24 (SEE CHART X) Preparation of 13,14-Dihydro-15-keto-PGE₂methyl ester (68), R: Et

24 - 1) Preparation of13,14-Dihydro-15,15-ethylenedioxy-11-(2-tetrahydropyranyl)-oxy-PGE₂ethyl ester (67):

The ethyl ester (10) (3.4 g) was oxidized with Jones reagent acetone(150 ml) at -40° C., and ketone (67) was obtained. Yield: 2.6 g.

24 - 2) Preparation of 13,14-Dihydro-15-keto-PGE₂ ethyl ester (68):

Ketone (67) (2.6 g) was dissolved in a mixed solvent (20 ml) of aceticacid: water: THF (4:2:1), and the solution was kept at 40°-50° C. for 3h. Following the usual procedures, there was obtained 1.4 g of13,14-dihydro-15-keto-PGE₂ ethyl ester (68).

The n. m. r. spectrum of 13,14-dihydro-15-keto-PGE₂ ethyl ester (68) isshown in FIG. 22.

EXAMPLE 25 (SEE CHART X) Preparation of 13,14-Dihydro-15-keto-PGE₂methyl ester (68), R=Me

The procedure of Example 24 was repeated, except that the carboxylicacid (9) was converted to the corresponding methyl ester (10) withdiazomethane, and thus 13,14-dihydro-15-keto-PGE₂ methyl ester (68),R=Me, was obtained.

The n. m. r. spectrum of 13,14-dihydro-15-keto-PGE₂ methyl ester (68) isshown in FIG. 23.

EXAMPLE 26 (SEE CHART X) Preparation of 13,14-Dihydro-15-keto-PGE₂n-propyl ester (68), R=n-Pro

The same procedure as in Examples 24 and 25 was followed, except thatthe carboxylic acid 9 was converted to the corresponding n-propyl ester(10) with DBU and n-propyl iodide in acetonitrile, and thus13,14-dihydro-15-keto-PGE₂ n-propyl ester (68) was obtained.

The n. m. r. spectrum of 13,14-dihydro-15-keto-PGE₂ n-propyl ester (68)is shown in FIG. 24.

EXAMPLE 27 (SEE CHART X) Preparation of 13,14-Dihydro-15-keto-PGE₂isopropyl ester (68), R=iso-Pro

The same procedure as in Examples 24, 25, and 26 was followed, exceptthat the carboxylic acid (9) was converted to the correspondingisopropyl ester (10) with DBU and isopropyl iodide in acetonitrile, andthus 13,14-dihydro-15-keto-PGE₂ isopropyl ester (68) was obtained.

The n. m. r. spectrum of the 13,14-dihydro-15-keto-PGE₂ isopropyl ester(68) is shown in FIG. 25.

EXAMPLE 28 (See Chart X) Preparation of 13,14-Dihydro-15-keto-PGE₂-n-butyl ester (68), R=n-Bu

The same procedure as in Examples 24, 25, 26, and 27 was followed,except that the carboxylic acid (9) was converted to the correspondingn-butyl-ester (10) with DBU and n-butyl iodide in acetonitrile, and thus13,14-dihydro-15-keto-PGE₂ n-butyl ester (68) was obtained.

The n. m. r. spectrum of 13,14-dihydro-15-keto-PGE₂ n-butyl ester (68)is shown in FIG. 26.

EXAMPLE 29 (SEE CHART X) Preparation of 13, 14-Dihydro-15-keto-PGE₂cyclopentyl ester (68), R=cyclopentyl

The same procedure as in Examples 24, 25, 26, 27, and 28 was followed,except that the carboxylic acid (9) was converted to the correspondingcyclopentyl-ester (10) with DBU and cyclopentyl iodide in acetonitrile,and thus 13,14-dihydro-15-keto-PGE₂ cyclopentyl ester (68) was obtained.

The n. m. r. spectrum of 13,14-dihydro-15-keto-PGE₂ cyclopentyl ester(68) is shown in FIG. 27.

EXAMPLE 30 (SEE CHART X) Preparation of 13,14-Dihydro-15-keto-PGE₂benzyl ester (68), R=Benzyl

The same procedure as in Examples 24, 25, 26, 27, 28, and 29 wasfollowed, except that the carboxylic acid (9) was converted to thecorresponding benzyl ester (10) with DBU and benzyl bromide inacetonitrile, and thus 13,14-dihydro-15-keto-PGE₂ -benzil ester (68) wasobtained.

The n. m. r. spectrum of 13,14-Dihydro-15-keto-PGE₂ benzyl ester (68) isshown in FIG. 28.

EXAMPLE 31 Preparation of 13,14-Dihydro-15-keto-16,16-dimethyl-PGE₂methyl ester (69), R=Me ##STR37##

The same procedure as in Examples 24 to 30 was followed using(-)-Coreylactone (1) and a dimethyl (3,3-dimethyl-2-oxoheptyl)phosphonateobtained in the ordinary method, to produce13,14-dihydro-15-keto-16,16-dimethyl-PGE₂ methyl ester (69).

The n. m. r. spectrum of 13,14-dihydro-15-keto-16,16-dimethyl-PGE₂methyl ester (69) is shown in FIG. 29.

EXAMPLE 32 Preparation of 13,14-Dihydro-15-keto-16,16-dimethyl-PGE₂ethyl ester (70), R=Et ##STR38##

The same procedure as in Examples 24 to 31 was followed using(-)-Coreylactone (1) and dimethyl (3,3-dimethyl-2-oxoheptyl)phosphonate toproduce 13,14-dihydro-15-keto-16,16-dimethyl-PGE₂ ethyl ester (70).

The n. m. r. spectrum of 13,14-Dihydro-15-keto-16,16-dimethyl-PGE₂ ethylester (70) is shown in FIG. 30.

EXAMPLE 33 (SEE CHARTS X AND XI) Preparation of 13,14-Dihydro-15-keto-3R,S-methyl-PGE₂ ethyl ester (74)

13,14-Dihydro-15-keto-3R,S-methyl-PGE₂ ethyl ester (74) was obtained byfollowing the same procedure as in Examples 24 to 30 except that ylideprepared from (3-methyl- 4-carboxybutyl)triphenylphosphonium bromide,and that the lactol (8), were used to produce13,14-dihydro-15,15-ethylenedioxy-3-methyl-11-(2-tetrahydropyranyl)oxy-PGF₂α(71).

The n. m. r. spectrum of 13,14-dihydro-15-keto-3 R,S-methyl-PGE₂ ethylester (74) is shown in FIG. 31.

EXAMPLE 34 (SEE CHARTS X AND XII) Preparation of13,14-Dihydro-15-keto-20-methoxy-PGE₂ methyl ester (79)

The same procedure as in Examples 24 to 30 was followed using(-)-Coreylactone (1) and dimethyl (7-methoxy-2-oxoheptyl)phosphonate produced inthe ordinary method, and thus 13,14-dihydro-15-keto-20-methoxy-PGE₂methyl ester (79) was obtained.

The n. m. r. spectrum of 13,14-dihydro-15-keto-20-methoxy-PGE₂ methylester (79) is shown in FIG. 32.

EXAMPLE 35 (SEE CHART XII) Preparation of13,14-Dihydro-15-keto-3R,S-methyl-20-methoxy-PGE₂ methyl ester (80)##STR39##

The same procedure as in examples 24 to 30, 33 and 34 was followed usinglactol (75) and (3-methyl-4-carboxybutyl) triphenylphosphonium bromideproduced in the usual manner, and thus13,14-Dihydro-15-keto-3R,S-methyl-20-methoxy-PGE₂ methyl ester (80) wasobtained.

The n. m. r. spectrum of13,14-Dihydro-15-keto-3R,S-methyl-20-methoxy-PGE₂ methyl ester (80) isshown in FIG. 33.

EXAMPLE 36 (SEE CHART XIII) Preparation of 13,14-Dihydro-15-keto-Δ²-PGE₂ methyl ester (85), R=H

36 - 1)11-(t-Butyldimethylsilyl)oxy-13,14-Dihydro-15,15-ethylenedioxy-2-phenylselecyl-PGF₂αmethyl ester (82):

LDA was prepared from diisopropyl- amine (0.13 ml) in dry THF (3 ml),and n-butyl lithium (1.6 - M; 0.58 ml), at -78° C. To LDA was added0.1850 g of (81) in THF, and stirred for 1.5 h. A dry THF solution (2ml) of diphenyl diselenide (0.18 g) was added, and the reaction solutionwas stirred at -78° C. for 30 min, then at room temperature for 1 h.Following usual procedure, there was obtained 0.1366 g of2-phenylselenyl-PGF₂α methyl ester (82).

36 - 2) Preparation of 11-(t-Butyldimethylsilyl)oxy-13,14-dihydro-15,15-ethylenedioxy-Δ² -PGF₂α methyl ester (83):

The 2-Phenylselenyl-PGF₂α methyl ester (82) (0.1366 g) was dissolved ina mixed solvent (4 ml) of ethyl acetate- THF (1:1), and sodium hydrogencarbonate (0.1 g) and 30% hydrogen pereoxide (0.3 ml) were added. Thereaction solution was stirred at room temperature for 15 min. Followingthe usual procedures, there was obtained 0.0850 g of11-(t-butyldimethylsilyl)oxy-13,14-dihydro-15,15-ethylene dioxy-Δ²-PGF₂α methyl ester (83). Yield: 0.0850 g.

36 - 3) Preparation of 11-(t-butyldimethylsilyl)oxy-13,14-Dihydro-15,15-ethylenedioxy-Δ² -PGE₂ methyl ester (84).

The Δ² -PGF₂α methyl ester (83) (0.0717 g) was oxidized with PCC onaluminum oxide (1 g) in benzene (2 ml). Following the usual procedures,there was obtained 0.0554 g of Δ² -PGE₂ methyl ester (84). Yield: 0.0554g.

36 - 4) Preparation of 13,14-Dihydro-15-keto-Δ² -PGE₂ methyl ester (85):

Δ² -PGE₂ methyl ester (84) (0.0554 g) was dissolved in acetonitrile (2ml), and a mixture (1.5 ml) of 46%-aqueous hydrogen fluoride andacetonitrile (1:2) was added. The reaction solution was stirred at roomtemperature for 50 min. Following the usual procedures, there wasobtained 13,14-Dihydro-15-keto-Δ² -PGE₂ methyl ester (85). Yield: 0.0312g.

The n. m. r. spectrum of 13,14-dihydro-15 keto-Δ² -PGE₂ methyl ester(85) is shown in FIG. 34.

EXAMPLE 37 (SEE CHART XIII) Preparation of13,14-Dihydro-15-keto-20-methoxy-Δ² -PGE₂ methyl ester (85), R=-OMe

The same procedure as in Examples 24 to 30, 34 and 36 was followed withusing(-)-Corey lactone (1) anddimethyl-(7-methoxy-2-oxoheptyl)phosphonate, and thus 13,14-dihydro-15-keto-20-methoxy-Δ² -PGE₂ methyl ester (85), R=- OMe, wasobtained.

The n. m. r. spectrum of 13,14-Dihydro-15-keto-20-methoxy-Δ² -PGE₂methyl ester (85) is shown in FIG. 35.

EXAMPLE 38 Preparation of 13,14-Dihydro-15-keto-18-methoxy-19,20-bisnor-PGE₂ methyl ester (86) ##STR40##

The same procedure as in Examples 24 to 30, and 34 was followed withusing(-)-Corey lactone (1) and dimethyl(5-methoxy-2-oxopentyl)phosphonate, and thus13,14-dihydro-15-keto-18-methoxy-19,20-bisnor-PGE₂ methyl ester (86) wasobtained.

The n. m. r. spectrum of13,14-Dihydro-15-keto-18-methoxy-19,20-bisnor-PGE₂ methyl ester (86) isshown in FIG. 36.

EXAMPLE 39 Preparation of 13,14-Dihydro-15-keto-20-ethyl-PGE₂ methylester (87), R=Me ##STR41##

The same procedure as in Examples 24 to 30 was followed withusing(-)-Corey lactone (1) and dimethyl(2-oxononyl)phosphonate, and thus13,14-dihydro-15-keto-20-ethyl-PGE₂ methyl ester (87) was obtained.

The n. m. r. spectrum of 13,14-Dihydro-15-keto-20-ethyl-PGE₂ -methylester (87) is shown in FIG. 37.

EXAMPLE 40 Preparation of 13,14-Dihydro-15-keto-20-ethyl-PGE₂ ethylester (87), R=Et ##STR42##

The same procedure as in Examples 24 to 28 was followed withusing(-)-Corey lactone (1) and dimethyl(2-oxononyl)phosphonate producedwith the known method, and thus 13,14-Dihydro-15-keto-20-ethyl-PGE₂ethyl ester (87) was obtained.

The n. m. r. spectrum of 13,14-Dihydro-15-keto-20-ethyl-PGE₂ -ethylester (87), R=Et, is shown in FIG. 38.

Mass(DI) m/z: 408, 390, 345.

EXAMPLE 41 (SEE THE STRUCTURAL FORMULA (87) SHOWN IN EXAMPLE 39)Preparation of 13,14-Dihydro-15-keto-20-ethyl-PGE₁ methyl ester (88)

13,14-Dihydro-15-keto-20-ethyl-PGE₂ methyl ester (87), R=Me, obtained inthe same way as in Example 39 was hydrogenated with plutinum oxide andhydrogen in ethanol, and thus 13,14-Dihydro-15-keto-20-ethyl-PGE₁ methylester (88) was prepared.

The n. m. r. spectrum of 13,14-Dihydro-15-keto-20-ethyl-PGE₁ methylester (88), R=Me, is shown in FIG. 39.

EXAMPLE 42 Preparation of 13,14-Dihydro-15-keto-20-n-propyl-PGE₂ methylester (89)

The same procedure as in Examples 24 to 30 and 39 was followedusing(-)-Corey lactone (1) and dimethyl(2-oxodecyl)phosphonate producedaccording to the known method, and thus13,14-Dihydro-15-keto-20-n-propyl-PGE₂ methyl ester (89) wassynthesized.

The n. m. r. spectrum of 13,14-Dihydro-15-keto-20-n-propyl-PGE₂ methylester (89) is shown in the FIG. 40.

Mass (SIMS): 409, 391, 369.

EXAMPLE 43 (SEE CHART XIV) Preparation of 13,14-Dihydro-15-keto-20-ethyl-11R-dehydroxy-11R-methyl-PGE₂ methyl ester (98)

43 - 1 ) Tosylation of1S-2Oxa-3-oxo-6R-(3,3-ethylenedioxy-1-decyl)-7R-hydroxy-cis-bicyclo(3,3,0)octane (90): Preparation of tosylate (91):

Alcohol (90) (1.723 g) was treated with p-toluenesulfonyl chloride(2.893 g) in pyridine (5 ml) to give the tosylate(91). Yield: 1.812 g(74%).

43 - 2) Preparation of 1S-2-Oxa-3-oxo-6S-(3,3-ethylenedioxy-1-decyl)-cis-bicyclo(3,3,0)oct-7-ene (92):

DBU (5.6 ml) was added to a toluene solution (1.9 ml) of the tosylate(91) (1.812 g), and the reaction solution was kept at 60° C. for 7 h. Acrude product obtained after the usual work-up was chromatographed(hexane-ethyl acetate=3:1) to give the olefin (92).

Yield: 0.7594 g (63%).

43 - 3) DIBAL-H reduction of1S-2-Oxa-3-oxo-6S-(3,3ethylenedioxy-1-decyl)-cis-bicyclo(3,3,0)-oct-7-ene(92): Preparation of lactol (93):

The olefin (92) (0.7594 g) was treated with DIBAL-H (1.5 - M; 6.2 ml) toproduce the lactol (93).

43 - 4) Preparation of methyl15,15-Ethylenedioxy-20-ethyl-9S-hydroxy-cis-Δ⁵ -Δ¹⁰ - prostanoate (95):

The lactol (93) was added to a ylide generated from(4-carboxybutyl)triphenylphosphonium bromide and sodium methylsulfinylcarbanion, in DMSO, whereby prostanoic acid (94) was obtained. The acid(94) was esterified with diazomethane, and thus methyl20-ethyl-prostanoate (95) was obtained.

Yield: 0.6600 g (67%).

43 - 5) Preparation of 15,15-Ethylenedioxy-20-ethyl-13,14-dihydro-PGA₂methyl ester (96):

The methyl 20-ethyl-prostanoate (95) (0.6600g) was oxidized with Jonesreagent in acetone (400 ml) at -20° C. The crude material obtained afterthe usual work-up was chromatographed (hexane-ethyl acetate=3:1) to give15,15-ethylenedioxy-20-ethyl-13,14-dihydro-PGA₂ methyl ester (96).

Yield: 0.6182 g (99%).

43 - 6) Preparation of15,15-Ethylenedioxy-20-ethyl-13,14-dihydro-11R-dehydroxy-11R-methyl PGE₂methyl ester (97):

The enone (96) (0.6100 g) was treated with lithium dimethylcuprateobtained from copper (I) iodide (0.8380 g) and methyl lithium (1.5 - M;5.8 ml), in ether (15 ml), and there was obtained15,15-ethylenedioxy-20-ethyl-13,14-dehydroxy-11R-dihydroxy-11R-methylPGE₂ methyl ester (97).

Yield: 0.5720 g (94%).

43 - 7) Preparation of13,14-Dihydro-15-keto-20-ethyl-11R-dehydroxy-11R-methyl-PGE₂ methylester (98):

15,15-Ethylenedioxy-20-ethyl-13,14-dihydro-11R-dehydroxy-11R-methyl-PGE.sub.2methyl ester (97) (0.2300 g) was dissolved in 25 ml of a mixed solventof acetic acid: water: THF (3:1:1), and the solution was kept at 50° C.for 2 h. A crude product obtained after the usual work-up waschromatographed to give13,14-dihydro-15-keto-20-ethyl-11R-dehydroxy-11R-methyl-PGE₂ methylester (98).

Yield: 0.200 g.

The n. m. r. spectrum of13,14-dihydro-15-keto-20-ethyl-11R-dehydroxy-11R-methyl-PGE₂ methylester (98) is shown in FIG. 41.

Mass (DI) m/z: 392, 374, 361, 343.

EXAMPLE 44 Preparation of13,14-Dihydro-15-keto-11R-dehydroxy-11R-methyl-PGE₂ ethyl ester (99)

The same procedure as in Example 43 was followed with using (-)-Coreylactone (1), dimethyl(2-oxoheptyl)phosphonate, and(4-carboxybutyl)triphenylphosphonium bromide, and 13,14-dihydro-15-keto-11R-dehydroxy-11R-methyl-PGE₂ ethyl ester (99) was produced.

The n. m. r. spectrum of13,14-dihydro-15-keto-11R-dehydroxy-11R-methyl-PGE₂ ethyl ester (99) isshown in FIG. 42.

Mass (SIMS) m/z: 387, 360, 333, 315.

EXAMPLE 45 (SEE CHART XV) Preparation of13,14-Dihydro-15-keto-20-isopropylidene-PGE₂ methyl ester (103)

1S-2-Oxa-3-oxo-6R-(8-isopropylidene-3-keto-1-trans-octenyl)-7R-(4-phenylbenzoyl)oxy-cis-bicyclo(3,3, 0)-octane (100), a compound produced from(-)-Corey lactone (1) anddimethyl (2-oxo-7-isopropylideneheptyl)phosphonate, was converted to thecorresponding silylenolether (101) with dimethylphenyl silane (0.9 ml)and Wilkinson catalyst (50 mg) in THF (40 ml). The silylenolether (101)was ketalized in benzene in the usual manner, and thus there wasobtained1S-2-oxa-3-oxo-6R-(8-isopropylidene-3,3-ethylenedioxy-1-octyl)-7R-(4-phenylbenzoyl)oxy-cis-bicyclo(3,3, 0)octane (102).

Yield: 2.32 g (82%).

Subsequently, the same procedure as in Examples 24 to 30, 40, 41, and 42was followed to produce 13,14-dihydro-15-keto-20-isopropylidene-PGE₂methyl ester (103).

The n. m. r. spectrum of 13,14-dihydro-15-keto-20-isopropylidene-PGE₂methyl ester (103) is shown in FIG. 43.

EXAMPLE 46 (SEE CHART XVI) Preparation of 13,14-Dihydro-6,15-diketo-PGE₁n-butyl ester (107), R=n - Bu

46 - 1) Preparation of the bromo-ether (104):

Bromo-ether formation from15,15-ethylenedioxy-13,14-dihidro-11-(2-tetrahydropyranyl)oxy-PGF₂.alpha.n-butyl ester (10):

The butyl ester (10) (1.165 g) was dissolved in a THF-dichloromethanemixture (3 ml+30 ml), and the solution was ice-cooled. After addition ofN-bromosuccinimide (0.405 g), the solution was stirred for 1 h. Thereaction solution was poured in aqueous dilute sodium sulfite, andextracted with dichloromethane. The extract was dried, then concentratedunder reduced pressure. The resulting crude product was chromatographedand thus bromo-ether (104) was obtained.

46 - 2) Preparation of15,15-Ethylenedioxy-13,14-dihydro-6-keto-11-(2-tetrahydropyranyl)oxy-PGF.sub.2αn-butyl ester (105):

Bromo-ether (104) (1.057 g) was dissolved in dry toluene (6 ml) and DBU(2.6 ml), and then agitated at 55° C. for 18 h. After being diluted withethyl acetate, the mixture was adjusted to pH 3. Then, the organic layerof the solution was processed in the usual way.

Yield: 0.7132 g (75%).

46 - 3) Preparation of15,15-Ethylenedioxy-13,14-dihydro-6-keto-11-(2-tetrahydropyranyl)oxy-PGE.sub.2n-butyl ester (106):

In acetone (40 ml), 6-keto-PGF₂α (105) (0.7132 g) was oxidized at -40°C. with Jones reagent, whereby13,14-dihydro-15,15-ethylenedioxy-6-keto-11-(2-tetrahydropyranyl)oxy-PGE.sub.2n-butyl ester (106) (0.4404 g) was obtained.

Yield: 0.4404 g (62%).

46 - 4) Preparation of 13,14-Dihydro-6,15-diketo-PGE₂ n-butyl ester(107):

13,14-Dihydro-15,15-ethylenedioxy-6-keto-11-(2-tetrahydropyranyloxy)-PGE.sub.2n-butyl ester (106) (0.4404 g) was kept at 55° C. in a mixed solvent ofacetic acid: THF: water (3:1:1) for 3.5 h, whereby there was obtained13,14-dihydro-6,15-diketo-PGE₂ n-butyl ester (107).

Yield: 0.200 g (59%).

The n. m. r. spectrum of 13,14-dihydro-6,15-diketo-PGE₂ n-butyl ester(107) is shown in the FIG. 44.

EXAMPLE 47 Preparation of 13,14-Dihydro-6,15-diketo-20-methyl-PGE₂ ethylester (108):

The procedure of Example 46 was repeated with using(-)-Corey lactone (1)and dimethyl(2-oxooctyl)phosphonate, and thus13,14-dihydro-6,15-diketo-20-methyl-PGE₂ ethyl ester (108) was obtained.

The n. m. r. spectrum of 13,14-dihydro-6,15-diketo- 20-methyl-PGE₂ ethylester (108) is shown in FIG. 45.

EXAMPLE 48 (SEE CHART XVII) Preparation of13,14-Dihydro-6,15-diketo-11R-dehydroxy-11 R-methyl PGE₁ ethyl ester(115), R=Et

48 - 1) Preparation of15,15-Ethylenedioxy-13,14-dihydro-11R-dehydroxy-11R-methyl-PGF₂.alpha.ethyl ester (110):

15,15-Ethylenedioxy-13,14-dihydro-11R-dehydroxy-11R-methyl PGE₂ ethylester (109) (1.775 g), the compound obtained in the same way as inExample 43, was dissolved in a THF-methanol mixed solvent, and 0.1600 gof NaBH₄ was added. The solution was kept at -18° C. overnight. A crudeproduct obtained after the usual work-up was chromatographed(hexane-ethyl acetate=3.5:1) to give.

9α-hydroxy substance (110): 0.9464 g;

9β-hydroxy substance (111): 0.5867 g.

The 9β-hydroxy substance (111) was oxidized with Jones reagent whereby15,15-ethylenedioxy-13,14-dihydro-11R-dehydroxy-11R-methyl PGE₂ ethylester (109) was recovered, which was again reduced with NaBH₄. Thesereaction were repeated to amount to 1.446 g of13,14-dihydro-15,15-ethylenedioxy-11R-dehydroxy-11 R-methyl-PGF₂α ethylester (110).

48 - 2) Preparation of Bromo-ether (112):

13,14-dihydro-15,15-ethylenedioxy-11R-dehydroxy- 11R-methyl-PGF₂α ethylester (110) (1.446 g) was dissolved in a mixed solvent of THF (12 ml)and dichloromethane (3.5 ml), and NBS (0.6453 g) was added at -18° C.Following the usual procedure, there was obtained 1.932 g of bromo-ether(112).

48 - 3) Preparation of15,15-Ethylenedioxy-13,14-dihydro-11R-dehydroxy-6-keto-11R-methyl-PGF.sub.2αethyl ester (113):

The bromo-ether (112) (1.932 g) was dissolved in DBU (6 ml) and toluene(3 ml), and the solution was kept at 75° C. A crude product obtainedafter the usual work-up was chromatographed (hexane-ethyl acetate=3:1)to give the title compound (113).

Yield: 1.230 g.

48 - 4) Preparation of15,15-Ethylenedioxy-13,14-dihydro-11R-dehydroxy-6-keto-11R-methyl-PGE.sub.1ethyl ester (114):

6-Keto-11R-methyl-PGF₂α ethyl ester (113) (1.230 g) was oxidized withJones reagent in acetone, whereby15,15-ethylenedioxy-13,14-dihydro-11R-dehydroxy-6-keto-11R-methyl-PGE.sub.1ethyl ester (114) was obtained.

Yield: 0.7614 g (62%) .

48 - 5) Preparation of13,14-Dihydro-6,15-diketo-11R-dehydroxy-11R-methyl-PGE₁ ethyl ester(115):

15,15-Ethylenedioxy-13,14-dihydro-11R-11R-dehydroxy-11R-methyl-PGE₁ethyl ester (114) (0.7614 g) was dissolved in a mixed solvent of aceticacid: THF: water (3:1:1), and the solution was kept at 50° C. for 5.Following the usual procedure, there was obtained 0.6290 g of13,14-dihydro-6,15-diketo-11R-dehydroxy-11R-methyl-PGE₁ ethyl ester(115), R=Et.

The n. m. r. spectrum of13,14-dihydro-6,15-diketo-11R-dehydroxy-11R-methyl-PGE₁ ethyl ester(115) is shown in FIG. 46.

Mass (SIMS): 395 (M+1)⁺, 377, 349.

EXAMPLE 49 (SEE CHART XVII) Preparation of13,14-Dihydro-6,15-diketo-11R-dehydroxy-11R-methyl-PGE₁ methyl ester(115), R=Me

The same procedure as in Example 48 was followed except thatdiazomethane was used for methyl-esterification, and thus there wasobtained 13,14-dihydro-6,15-diketo-11R-dehydroxy-11R-methyl-PGE₁ methylester (115), R=Me.

The n. m. r. spectrum of13,14-dihydro-6,15-diketo-11R-dehydroxy-11R-methyl-PGE₁ methyl ester(115), R=Me, is shown in FIG. 47.

Mass (DI): 380, 362, 349, 331.

EXAMPLE 50 (SEE CHART XVIII) Preparation of13,14-Dihydro-15-keto-16R,S-fluoro-PGE₂ methyl ester (125), R=Me

50 - 1) Preparation of1S-2-oxa-3-oxo-6R-(4-fluoro-3-keto-1-octyl-7R-hydroxy-cis-bicyclo(3, 3,0)octane (118):

A saturated ketone (117) (5.20 g) obtained after catalytic hydrogenationof the unsaturated ketone (116) produced from(-)-Corey lactone (1) anddimethyl(3-fluoro-2-oxoheptyl)phosphonate was dissolved in a mixedsolvent (18 ml) of THF and methanol (3:1), and potassium carbonate (1.54g) was added. The solution was stirred for 3 h.

The crude product obtained after the usual work-up was chromatographed(hexane: ethyl acetate=1:1) to yield an alcohol (118).

Yield: 1.81 g (57%).

50 - 2) Preparation of1S-2-Oxa-3-oxo-6R-(4R,S-fluoro-3-oxo-1-octyl)-7R-(2-tetrahydropyranyl)oxy-cis-bicycle-(3,3, 0) octane (119):

The alcohol (118) (1.81 g) was converted to the correspondingtetrahydropyranyl ether (119) with dihydrapyran and p-toluenesulfonicacid in dichloromethane.

Yield: 2.33 g.

50 - 3) Preparation of1S-2-Oxa-3-oxo-6R-(4R,S-fluoro-3R,S-hydroxy-1-octyl)-7R-(2-tetrahydropyranyl)oxy-cis-bicyclo-(3, 3, 0)octane (120):

The tetrahydropyranyl ether (119) (2.33 g) was reduced with NaBH₄ inmethanol. Alcoholic-lactone (120) was thus obtained.

50 - 4) Preparation of Lactol (121):

The alcoholic-lactone (120) (0.84 g) was reduced with DIBAL-H (1.5 - M,6 ml) in toluene (20 ml) to the corresponding lactol (121).

50 - 5) Preparation of16R,S-fluoro-13,14-dihydro-15R,S-hydroxy-11R-(2-tetrahydropyranyl)oxy-PGF.sub.2αmethyl ester (123), R=Me:

Ylide produced from (4-carboxybutyl)triphenyl˜phosphonium bromide (3.50g) in the ordinary method was let to react with the previouslysynthesized lactol (121) in DMSO. A carboxylic acid (122) obtainedaccording to the ordinary procedure was treated with diazomethane.Methyl ester (123) was thus obtained.

Yield: 0.470 g (44%).

50 - 6) Preparation of 13,14-Dihydro-15-keto-16R,S-fluoro-PGE₂ methylester (125), R=Me:

The methyl ester (123) (0.470) was oxidized with Jones reagent inacetone (25 ml) at -30° C. After the usual work-up, the crude productwas charomatographed (hexane: ethyl acetate=5:2) to yield 0.298 g of13,14-dihydro-15-keto-16R,S-fluoro-11R-(2-tetrahydropyranyl)oxy-PGE₂methyl ester (124).

The methyl ester (124) (0.296 g) was dissolved in a mixed solvent (25ml) of acetic acid, THF, and water (4:1:2), and the solution was kept at45° C. for 3 h. Then, a crude product obtained after the usual work-upwas chromatographed (benzene - ethyl acetate=2:3) to give13,14-dihydro-15-keto-16R,S-fluoro-PGE₂ methyl ester (125), R=Me.

Yield: 0.202 g.

The n. m. r. spectrum of 13,14dihydro-15-keto- 16-R,S-fluoro-PGE₂ methylester (125) is shown in FIG. 48.

Mass (DI) 384, 366, 346, 335.

EXAMPLE 51 (SEE CHART XIX) Preparation of13,14-Dihydro-6,15-diketo-16R,S-fluoro-11R-dehydroxy-11R-methyl-PGE₁ethyl ester (135)

51 - 1) Tosylation of16R,S-Fluoro-13,14-dihydro-15R,S-(t-butyldimethylsilyl)oxy-PGF₂.alpha.ethyl ester (126):

Preparation of tosylate (127):16R,S-Fluoro-13,14-dihydro-15R,S-(t-butyldimethylsilyl)oxy-PGF₂.alpha.ethyl ester (126) (1.00 g) produced from(-)-Corey lactone (1) anddimethyl(3-fluoro-2-oxoheptyl)phosphonate according to the known methodwas tosylated with tosyl chloride (4.00 g) in pyridine (10 ml) at 0° C.

Yield: 1.04 g.

51 - 2) Preparation of16R,S-fluoro-13,14-dihydro-15R,S-(t-butyldimethylsilyl)oxy-PGA₂ ethylester (128):

The tosylate (127) (1.04 g) was oxidized with Jones reagent (2.67- M, 2ml) in acetone (30 ml) at -20° C. A crude product obtained after usualprocessing was chromatographed (hexane-ethyl acetate=5:1) to give16R,S-fluoro-13,14-dihydro-15R,S-(t-butyldimethylsilyl)oxy-PGA₂ ethylester (128).

Yield: 0.627 g.

51 - 3) Preparation of 16R,S-Fluoro-13,14-dihydro-11R-dehydroxy-11R-methyl-15R,S-(t-butyldimethylsilyl)oxy-PGE₂ ethylester (129):

To lithium dimethylcuprate, prepared in ether (70 ml) from copper (I)iodide (1.28 g) and methyl lithium (1.5-M, 9.0 ml) was added an ethersolution (40 ml) of the enone (128) (1.114 g). The mixture was stirredfor 30 min. Then, after usual processing, there was obtained16R,S-fluoro-13,14-dihydro-11R-dehydroxy-11R,-methyl-15R,S-t-butyldimethylsilyl)oxy-PGE₂ethyl ester (129).

Yield: 0.931 g.

51 - 4) Preparation of16R,S-Fluoro-13,14-dihydro-11R-dehydroxy-11R-methyl-15R,S-(t-butyldimethylsilyl)oxy-PGF₂α ethyl ester (130):

The ketone (129) (0.931 g) was reduced with NaBH₄ (0.688 g) in methanol(40 ml), and thus 9α-hydroxy-PGF derivative (130) and 9β-hydroxy-PGFderivative (131) were obtained.

The 9β-hydroxy-PGF derivative (131) was oxidized by Jones reagent to theketone (129), and then reduction of the ketone (129) with NaBH₄ wascarried out again. A total yield of 0.677 g of16R,S-fluoro-13,14-dihydro-11R-dehydroxy-11R-methyl-15R,S-(t-butyldimethylsilyl)oxy-PGF₂αethyl ester (130) was obtained.

51 - 5) Preparation of16R,S-Fluoro-13,14-dihydro-11R-dehydroxy-15R,S-hydroxy-11R-methyl-PGF.sub.2αethyl ester (132):

Tetrabutylammonium fluoride (1.0 - M; 8 ml) was added to a THF solutionof 15R,S-(t-butyldimethylsilyl)oxy-PGF₂α ethyl ester (130) (0.677 g),and the mixture was stirred at room temperature overnight. A crudeproduct obtained after the usual processing was chromatographed(hexane-ethyl acetate=3:1) to give16R,S-fluoro-13,14-dihydro-11R-dehydroxy-15R,S-hydroxy-11R-methyl-PGF.sub.2αethyl ester (132) (0.503 g).

51 - 6) Preparation of13,14-Dihydro-6,15-diketo-16R,S-fluoro-11R-dehydroxy-11R-methyl-PGE₁ethyl ester (135):

The same procedure as in Examples 48 and 49 was followed with using16R,S-fluoro-13,14-dihydro-11R-dehydroxy-15R,S- hydroxy-11R-methyl-PGF₂α ethyl ester (132), and thus there was obtained13,14-dihydro-6,15-diketo-11R-dehydroxy-11R-methyl-PGE₁ ethyl ester(135).

The n. m. r. spectrum of13,14-dihydro-6,15-diketo-11R-dehydroxy-11R-methyl-PGE₁ ethyl ester(135) is shown in FIG. 49.

Mass (DI): 412, 394, 367.

EXAMPLE 52 (SEE CHART XX) Preparation of13,14-Dihydro-6,15-diketo-11R-dehydroxy-11R-hydroxymethyl-19-methyl-PGE.sub.1methyl ester (138)

52 - 1) Preparation of15,15-Ethylenedioxy-13,14-dihidro-11R-dehydroxy-11R-hydroxymethyl-PGE.sub.2methyl ester (137):

15,15-Ethylenedioxy-13,14-dihydro-19-methyl-PGA₂ methyl ester (136)(0.410 g) produced from (-)-Corey lactone (1) anddimethyl(6-methyl-2-oxoheptyl)phosphonate, and 0.255 g of benzophenonewere dissolved in 80 ml of methanol. The solution was irradiated througha pyrex filter with a 300 W high pressure mercury lamp. After theordinary work-up and purification, there was obtained 15,15-ethylenedioxy-13,14-dihidro-11R-dehydroxy-11R-hydroxymethyl-19-methyl-PGE₂methyl ester (137).

52 -2) Preparation of13,14-Dihydro-6,15-diketo-11R-dehydroxy-11R-hydroxymethyl-19-methyl-PGE.sub.1methyl ester (138):

The same procedure as in Examples 47, 48, and 49 was applied on thecompound (137) and thus13,14-dihydro-6,15-diketo-11R-dehydroxy-11R-hydroxymethyl-19-methyl-PGE.sub.1methyl ester (138) was obtained.

In FIG. 51 there is shown the n. m. r. spectrum of13,14-dihydro-6,15-diketo-11R-dehydroxy-11R-hydroxymethyl-19-methyl-PGE.sub.1methyl ester (138) is shown in FIG. 50

Mass m/z 410 (M⁺), 392(M⁺ -18), 379, 361.

EXAMPLE 53 (SEE CHART XXI) Preparation of13,14-Dihydro-15-keto-16R,S-fluoro-PGE₂ (140)

53-1) Preparation of13,14-Dihydro-15-keto-16R,S-fluoro-11R-(2-tetrahydropyranyl)oxy-PGE₂(139):

The carboxylic acid (122) was oxidized in aceton (25 ml) with Jonesreagent (2.67-M, 1.1 ml) at -15° C. A crude product obtained after theusual work-up was chromatographed to give13,14-dihydro-15-keto-16R,S-fluoro-11R-(2-tetrahydropyranyl)oxy-PGE₂(139). Yield: 0.247 g.

53-2) Preparation of 13,14-Dihydro-15-keto-16R,S-fluoro-PGE₂ (140):

13,14-Dihydro-15-keto-16R,S-fluoro-11R-(2-tetrahydropyranyl)oxy-PGE₂(139) (0.247 g) was dissolved in a mixture (25 ml) of acetic acid -water - THF (4:2:1) to be kept at 45° C. for 3 h. A crude productobtained after the usual work-up was chromatographed to give13,14-dihydro-15-keto 16R,S-fluoro-PGE₂ (140). Yield: 0.148 g.

The n. m. r. spectrum of 13,14-dihydro-15-keto-16R,S-fluoro-PGE₂ (140)is shown. in FIG. 51.

Mass 352 (M⁺ -18) 282, 281, 226. C¹³ -n.m.r. was determined using a 400MHz device. The results are as follows:

Apparent from the above C¹³ -n.m.r. the above compound (140) formspossibly following equilibrium mixture of tautomeric isomers. ##STR43##

    ______________________________________                                        No.           PPM     INT (%)                                                 ______________________________________                                         1            215.845 8.47238                                                  2            213.758 8.04458                                                  3            210.693 5.10931                                                  4            210.460 3.59663                                                  5            210.357 3.26243                                                  6            178.890 8.35974                                                  7            178.700 9.36714                                                  8            131.032 18.77798                                                 9            130.580 16.85946                                                10            127.135 17.49468                                                11            126.960 20.51506                                                12            97.960  4.23425                                                 13            97.799  5.10057                                                 14            97.609  3.64508                                                 15            97.376  4.06103                                                 16            97.171  4.59381                                                 17            96.996  8.52154                                                 18            96.310  5.02938                                                 19            96.208  4.25401                                                 20            95.157  8.06931                                                 21            77.351  98.89423                                                22            77.030  100.00000                                               23            76.709  94.29728                                                24            72.929  19.24167                                                25            71.294  9.80660                                                 26            71.207  8.76754                                                 27            65.821  3.16846                                                 28            53.999  28.13616                                                29            53.181  18.97531                                                30            47.869  24.43601                                                31            47.051  23.90225                                                32            45.986  12.52490                                                33            45.869  12.09867                                                34            43.753  14.28856                                                35            35.492  16.17178                                                36            33.492  2.97718                                                 37            33.230  31.33004                                                38            31.829  16.02193                                                39            31.624  16.87059                                                40            29.858  10.79520                                                41            29.712  3.99469                                                 42            29.581  11.04714                                                43            28.866  7.22944                                                 44            28.647  6.83104                                                 45            28.515  7.46747                                                 46            28.297  6.62025                                                 47            27.786  12.35639                                                48            27.246  9.17236                                                 49            26.662  28.41152                                                50            26.458  29.42895                                                51            24.823  29.72020                                                52            24.575  3.98072                                                 53            24.458  41.26676                                                54            23.714  16.46572                                                55            23.655  11.84843                                                56            22.415  17.92916                                                57            22.225  34.46823                                                58            15.175  3.38720                                                 59            13.906  16.04726                                                60            13.774  23.45338                                                ______________________________________                                    

EXAMPLE 54 Preparation of 13,14-Dihydro-15-keto-20-methyl-PGE₁ methylester (141) ##STR44##

13,14-Dihydro-15-keto-20-methyl-PGE₁ methyl ester (141) was preparedusing (-)-Corey lactone together with dimethyl(2-oxooctyl)phosphonateaccording to the procedure as in Example 41.

The n.m.r. spectrum of the titled compound (141) was shown in FIG. 52.

Mass (DI) m/z 382(M⁺), 364, 333.

EXAMPLE 55 (SEE CHART XXII) Preparation of 13,14-Dihydro-15-keto-Δ²-PGE₁ methyl ester (146)

According to the same manner as in Example 36 13,14-dihydro-15-keto-Δ²-PGE₁ methyl ester (146) was prepared using13,14-dihydro-15,15-ethylenedioxy-11-(2-tetrahydropyranyl)oxy-PGF₁.alpha.methyl ester (142) which can be obtained by catalitic hydrogenation ofthe compound (10).

The n.m.r. spectrum of the titled compound (146) is shown in FIG. 53.

Mass (DI) z/m 366, 348, 316.

EXAMPLE 56 (SEE CHART XXII) Preparation of 13,14-Dihydro-15-keto-Δ²-PGE₁ (149)

56-1 Preparation of13,14-Dihydro-15,15-ethylenedioxy-11-(2-tetrahydropyranyl)oxy-Δ.sup.2-PGF₁α (147):

To the solution of13,14-dihydro-15,15-ethylenedioxy-11-(2-tetrahydropyranyl)oxy-Δ.sup.2-PGF₁α methyl ester (144) (0.7687 g) in THF (15 ml) 0.5-M aqueoussolution of litium hydroxide (20 ml) was added, and stirred at roomtemperature over night. A crude carboxylic acid (147) was obtained aftera usual work-up. Yield: 0.8779 g.

56-2 Preparation of 13,14-Dihydro-15,15-ethylenedioxy-11-(2-tetrahydropyranyl)oxy-Δ² PGE₁α (148):

Carboxylic acid (147) (0.8779 g) was oxidized with Jones reagent(2.67-M, 1.7 ml) at -35° C. in acetone (50 ml). A crude product obtainedafter a usual work-up was chromatographed (3-5% isopropanol-hexane) togive 13,14-dihydro-15,15-ethylenedioxy-11-(2-tetrahydropyranyl) oxy-Δ²-PGE₁ (148). Yield: 0.5972 g.

56-3 Preparation of 13,14-Dihydro-15-keto-Δ² -PGE₁ (149):

In a mixed solvent of acetic acid:THF:water (3:1:1) (15 ml) Δ² -PGE₁(148) (0.5972 g) was dissolved and maintained at 40° C. for 3.5 hours. Acrude compound obtained by a usual work-up was chromatographed twice(acid washed Mallincklodt silica-gel, hexane:ethyl acetate=3:1-1:1, andthen 8% isopropanol-hexane) to give 13,14-dihydro-15-keto-Δ² -PGE₁(149). Yield: 0.2473.

The n.m.r. of the titled compound (149) was shown in FIG. 54.

Mass (DI) z/m 352(M⁺), 334, 316.

EXAMPLE 57 Preparation of13,14-Dihydro-15-keto-16R,S-fluoro-20-methyl-PGE₂ methyl ester (150)##STR45##

Using (-)-Corey lactone and dimethyl(3R,S-fluoro-2-oxooctyl)phosphonate,13,14-dihydro-15-keto-16R,S-fluoro-20-methyl-PGE₂ methyl ester (150) wasprepared according to the same manner as in Example 50.

The n.m.r. spectrum of the titled compound (150) was shown in FIG. 55.

Mass (DI) m/z 398(M⁺), 380.

EXAMPLE 58 (SEE CHART XXIII) Preparation of13,14-Dihydro-15-keto-16,16-difluoro-PGE₂ methyl ester (160):

58-1 Preparation of1S-2-Oxa-3-oxo-6R-(4,4-difluoro-3-oxo-trans-1-octenyl)-7R-(4-phenylbenzoyl)oxy-cis-bicyclo(3,3,0)octane(151):

Aldehyde (2) was obtained by the oxidation of (-)-Corey lactone (1)(6.33 g) with Collins reagent. Separately thallium ethoxide (4.26 g) wasdissolved in benzene, to which the solution ofdimethyl(3,3-difluoro-2-oxoheptyl)phosphonate (4.64 g) in benzene wasadded at cool temperature, and the mixture was stirred for 30 min. Tothe resultant the solution of the aldehyde (2) in benzene as preparedabove was added, and stirred at room temperature for 3 h. After themixture was neutralized with acetic acid, a saturated aqueous solutionof potassium iodide was added and passed through a celite column. Aftera usual work-up the desired unsaturated ketone (151) was obtained.Yield: 3.88 g.

58-2 Preparation of1S-2-Oxa-3-oxo-6R-(4,4-difluoro-3R,S-hydroxy-1-octyl)-7R-(4-phenylbenzoyl)oxy-cis-bicyclo(3,3,0)octane(153):

The unsaturated ketone (151) (3.88 g) was hydrogenated with palladium oncarbon (5%) in ethyl acetate (40 ml) to give the saturated ketone (152).The saturated ketone (152) was reduced with NaBH₄ in a mixed solvent ofmethanol-THF (70:30) to give the alcohol (153). Yield: 4.02 g.

58-3 Preparation of1S-2-Oxa-3-oxo-6R-(4,4-difluoro-15R,S-t-butyldimethylsilyloxy-1-octyl)-7R-hydroxy-cis-bicyclo(3,3,0)octane(155):

The alcohol (153) was treated with imidazol and t-butyldimethylsilylchloride in DMF to give1S-2-oxa-3-oxo-6R-(4,4-difluoro-15R,S-t-butyldimethylsilyloxy-1-octyl)-7R-(4-phenylbenzoyl)oxy-cis-bicyclo(3.3.0)octane (154). The resultant (154) was methonolysised with potassiumcarbonate (1.14 g) in methanol (20 ml) to give1S-2-oxa-3-oxo-6R-(4,4-difluoro-15R,S-t-butyldimethylsilyloxy-1-octyl)-7R-hydroxy-cis-bicyclo(3,3,0)octane (155). Yield: 2.89 g.

58-4 Preparation of1S-2-Oxa-3-oxo-6R-(4,4-difluoro-15R,S-t-butyldimethylsilyloxy-1-octyl)-7R-(2-tetrahydropyranyl)oxy-cis-bicyclo(3,3,0)octane(156):

The alcohol (155) was converted to the tetrahydropyranyl ether (156)according to a known method. Yield: 3.38 g.

58-5 Preparation of16,16-difluoro-13,14-dihydro-15R,S-t-butyldimethylsilyloxy-11-(2-tetrahydropyranyl)oxy-PGF₂αmethyl ester (157):

The desired silylether (157) was obtained from the tetrahydropyranylether (156) (3.38 g) according to the procedure in Examples 50 and 51.Yield: 3.02 g.

58-6 Preparation of16,16-Difluoro-13,14-dihydro-15R,S-hydroxy-11R-(2-tetrahydropyranyl)oxy-PGF₂αmethyl ester (158):

The silyl ether (157) (0.882 g) was treated with tetrabutylammoniumfluoride (1.1-M, 10.6 ml) in THF (25 ml) to give the desired diol (158).Yield: 0.710 g.

58-7 Preparation of 13,14-Dihydro-15-keto-16,16-difluoro-PGE₂ methylester (160):

Collins reagent was prepared from chromic anhydride (2.57 g) andpyridine (4.15 nil) in dichloromethane (40 ml). To the resultant wasadded the solution of the diol (158) (0.360 g) in dichloromethane (15ml). After the usual work-up and purification,13,14-dihydro-15-keto-16,16-difluoro-11-(2-tetrahydropyranyl)oxy-PGE₂methyl ester (159) was obtained. Yield: 0.277 g. The obtained compound(159) (0.208 g) was dissolved in a mixed solvent of acetic acid:THF:water (4:2:1) (30 ml) and maintained at 45° C. for 3.5 h. A crudecompound obtained after a usual work-up was chromatographed to give13,14-dihydro-15-keto-16,16-difluoro-PGE₂ methyl ester (160). Yield:0.208 g.

The n.m.r. spectrum of the titled compound (160) is shown in FIG. 56.

Mass (DI) z/m 402(M⁺), 384(M⁺ -18), 364.

EXAMPLE 59 (SEE CHARTS XXIV AND XXV) Preparation of13,14-dihydro-15-keto-5,6-dehydro-20-methoxy-PGE₂ methyl ester (141)

To a solution of 8-methoxy-3,3-ethylenedioxy-1-iodooctane (167) (0.985g) in ether (15 ml) t-butyllitium (2.3-M, 2.87 ml) was added dropwise at-78° C., and the resultant mixture was stirred for 3 h, to which anether solution of copper (I) iodide and tributylphosphine was added allat once, and stirred for 20 min. To the reaction mixture was added asolution of 4R-t-butyldimethylsilyloxy-2-cyclopentene-1-on (168) (0.637g) in THF (21 ml) dropwise over 15 min. After 15 min HMPA (2.61 ml) wasadded to the resultant followed by the addition of triphenyltin chloride(1.217 g) in THF (6 ml) after 30 min, and then stirred for 15 min. Thereaction mixture was cooled at -30° C., to which a solution of6-carboxymethoxy-1-iodo-2-hexyne (169) (3.19 g) in HPMA (2.61 ml) wasadded, and stirred for 4.5 h and then at room temperature for 12 h. Thereaction mixture was poured into a saturated ammonium chloride solutionwith vigorous agitation. The organic layer was collected. The aqueouslayer was extracted with ether, and the extracted layer was put togetherwith the organic layer, which was then washed with a saturated aqueoussolution of sodium chloride. After dried the organic layer wasconcentrated under reduced pressure to give a crude product. The crudeproduct was chromatographed to give11-t-butyldimethylsilyloxy-15,15-ethylenedioxy-13,14-dihydro-5,6-dehydro-20-methoxy-PGE₂methyl ester (170). Yield: 0.3700 g.

n.m.r.: 0.08(3H,s), 0.10(3H,s), 1.3-2.8(24H, m), 3.30 (3H,s),3.32(2H,t), 3.74(3H,s), 3.90(4H,s), 4.10(1H,m).

59-2 Preparation of 13,14-dihydro-15-keto-5,6-dehydro-20-methoxy-PGE₂methyl ester (171):

A mixture (3 ml) of hydrofluoric acid (46%): acetonitrile (1:2) cooledat 0° C. was added to11-t-butyldimethylsilyloxy-15,15-ethylenedioxy-13,14-dihydro-5,6-dehydro-20-methoxy-PGE₂methyl ester (170) (0.035 g), and stirred at room temperature for 25min, to which water was poured, and the reaction product was extractedwith ethyl acetate. The obtained organic layer was neutralized with asaturated aqueous solution of sodium bicarbonate, and concentrated underreduced pressure to give a crude product, which was chromatographed togive 13,14-dihydro-15-keto-5,6-dehydro-20-methoxy-PGE₂ methyl ester(171). Yield: 0.0081 g.

The n.m.r. spectrum of the obtained compound (171) was shown in FIG. 57.

EXAMPLE 60 (SEE CHART XXVI) Preparation of13,14-dihydro-15-keto-16R,S,16R,S-difluoro-PGE₂ (174)

60-1 synthesis of13,14-dihydro-15R,S-hydroxy-11R-(2-tetrahydropyranyl)oxy-16,16-difluoro-PGE₂(172):

13,14-dihydro-15R,S-hydroxy-11R-(2-tetrahydropyranyl)oxy-16,16-difluoro-PGE₂methyl ester (158) (0.731 g) was dissolved in sodium hydroxide:methanol(1:3) solution (60 ml), and stirred at room temperature for 5 hours. Theresultant was treated by a usual work-up to give a crude carbonylic acid(172). Yield: 0.722 g.

60-2 synthesis of 13,14-dihydro-15-keto-16,16-difluoro-PGE₂ (174):

The title compound (174) was prepared according to the same manner asthe process 58-7 in the Example 58 excepting using the compound (172)(0.722g) instead of the compound (158). Yield: 0.192 g.

The n.m.r. spectrum of the title compound (174) is as follows: ¹ H NMR(200 MHz, CDCl₃) δ0.93 (3H, t, J=7.1 Hz), 1.23-2.98 (22H, m), 4.11-4.28(1H, m C(11)H), 5.34-5.48 (2H, m).

Mass (m/z) 388 (M+), 370 (M+-H₂ O).

Existence of the hemiacetal is confirmed by C¹³ n.m.r. spectrum of thecompound (174).

The n.m.r. data of compounds in the above Examples are shown as follows,wherein the compounds number in brackets.

(6) δ: 0.88 (3H, 6 Hz), 1.1-3.0(19H, m), 3.8-4.1(1H, m), 3.90(4H, s),4.93(1H, dt, J=6 Hz, J=3 Hz)

(7) 0.88(3H, 6 Hz), 1.0-2.9(24H, m), 350(1H, m), 3.88(4H, s),3.6-4.1(2H, m), 4.63(1H, bs), 4.8-5.06(1H, m)

(11) 0.88(3H, t, J=6 Hz), 1.24(3H, t, J=7.5 Hz), 1.0-2.7(30H, m),3.3-3.6(1H, m), 3.89(4H, s), 3.6-4.35(5H, m), 4.10(2H, q, 8.75 Hz),4.35-4.7(1H, m)

(23) 0.7-1.0(6H, m), 1.0-3.0(18H, m), 3.8-4.1(1H), 3.90(4H, s), 4.92(1H,dt, J=6 Hz, J=3 Hz)

(30) 0.73-1.0(6H, m), 1.24(3H, t, J=7 Hz), 1.0-2.5(29H, m), 3.3-4.7(7H,m), 3.88(4H, s), 4.11(2H, q, J=7 Hz)

(38) 0.88(3H, t, J=6 Hz), 1.1-3.6(16H, m), 4.43(0.5H, t, J=6 Hz),4.9-5.3(2.5H, m), 7.3-8.2(9H, m)

(39) 0.90(3H, t, J=6 Hz), 1.1-3.2(17H, m), 3.3-3.8(1H, m),3.8-4.16(0.5H, m), 4.33-4.75(0.5H, m), 4.9-5.16(1H, bs), 5.16-5.33(1H,m), 7.3-8.2(9H, m)

(40) 0.07(6H, S), 0.87(9H, S), 0.7-1.05(3H), 1.05-3.2(16H, m),3.5-3.85(1H, m), 3.85-4.15(0.5H, m), 4.3-4.6(0.5H, m), 4.95-5.15(1H, m)5.15-5.33(1H, m), 7.3-8.2(9H, m)

(41) 0.07(6H, s), 0.88(9,H, S), 0.75-1.05(3H), 1.05-3.0(17H, m),3.45-3.85(1H, m), 3.85-4.15(1.5H, m), 4.4-4.65(0.5H, m), 4.93(1H, dd,J=6 Hz, J=3 Hz)

(42) 0.05(6H, s), 0.88(9H,s), 0.75-1.05(3H), 1.05-3.0(22H, m),3.3-5.1(7H, m)

(45) 0.07(6H, s), 0.88(9H, S), 0.75-1.0(3H), 1.23(3H, t, J=7 Hz),1.05-2.6(29H, m), 3.2-4.7(7H, m), 4.07(2H, q, J=7Hz), 5.1-5.65(2H, m)

(46) 0.88(3H, t, J=6 Hz), 1.23(3H, t, J=7 Hz), 1.1-2.6(30H, m),3.3-4.2(6H, m), 4.10(2H, q, J=7 Hz), 4.60(1H, bS), 5.1-5.7(2H, m)

(47) 0.90(3H, t, J=6Hz), 1.25(3H, t, J=6 Hz), 1.03-2.70(29H, m),3.25-4,70(9H, m), 4.07(2H, q, J=6 Hz)

(52) 0.92(3H, t, J=6 Hz), 1.24(3H, t, J=6 Hz), 1.05-2.75(21H, m),3.3-3.8(1H, m), 4.10(2H, q, 6 Hz), 4.10(0.5H), 4.4-4.7(0.5H, m),5.67(2H, m), 6.10(1H, dd, J=6 Hz, J=3Hz), 7.57(1H, dd, J=6 Hz, J=3Hz)

(92) 0.88(3H, t, J=6Hz), 1.1-1.8(16H, m), 2.2-3.0(4H, m), 3.88(4H, s),5.4-5.57(1H, m), 5.80(1H, dd, J=6 Hz, J=3 Hz), 6.02(1H, dd, J=6 Hz, 3Hz)

(95) 0.88(3H, t, J=6Hz), 1.0-2.6(27H, m), 3.62(3H, s), 3.88(4H, S),4.5-4.7(1H, m), 5.1-5.6(2H, m), 5.6-6.0(2H, m)

(96) 0.87(3H, t, J=6 Hz), 1.1-2.7(26H, m), 3.62(3H, S), 3.87(4H, S),5.15-5.60(2H, m), 6.07(1H, dd, J=6 Hz, J=3 Hz), 7.53(1H, dd, J=6 Hz, J=3Hz)

(97) 0.87(3H, t, J=6Hz), 1.10(3H, d, J=5Hz), 1.0-2.7(29H, m), 3.62(3H,S), 3.7-4.0(4H), 5.1-5.6(2H, m)

(104) 0.7-1.03(6H, m), 1.03-2.6(34H, m), 3.3-4.3(6H, m), 3.88(4H, S),4.08(2H, q, J=7Hz), 4.60(1H, m)

(112) 0.88(3H, t, J=6 Hz), 0.97(3H, d, J=6 Hz), 1.23(3H, t, J=7Hz),1.1-2.5(25H, m), 3.90(4H, s), 4.10(2H, q, J=7 Hz), 3.8-4.7(3H, m)

(118) 0.90(3H, t, J=6 Hz), 1.1-3.1(17H, m), 3.93(1H, q, J=6 Hz),4.41(0.5H, t, J=6 Hz), 4.7-5.1(1.5H, m)

(127) 0.05(6H, s), 0.88(9H, s), 0.75-1.0(3H), 1.23(3H, t, J=7 Hz),1.05-2,4(23H, m), 2,42(3H, s), 4.08(2H, q, J=7 Hz), 3.9-4.7(4H, m),5.35(2H, m), 7.27(2H, d, J=9 Hz), 7.75(2H, d, J=9 Hz)

(129) 0.05(6H, s), 0.88(9H, s), 0.7-1.0(3H), 1.23 (3H, t, J=7 Hz),1.05-2.65(20H, m), 3.4-3.85(1H, m), 4.07(2H, q, J=7Hz), 3.85-4.15(0.5H),4.35-4.65(0.5H, m) 5.35(2H, m), 6.08(1H, dd, J=6Hz, J=3Hz), 7.53(1H, dd,J=6 Hz, J=3 Hz)

(137) 0.85(6H, d, J=7 Hz), 1.0-2.7(25H, m), 3.62(3H, S), 3.5-3.75(2H),3.88(4H, s), 5.1-5.6(2H, m)

The above data were determined by n.m.r. measuring apparatus R-90Havailable from Hitachi Seisakusho.

TEST EXAMPLE 1 Antiulcer Activity

As test samples, we used the PGE as obtained in Examples 2 to 52 asdescribed herein, 13,14-dihydro-15-keto-PGE.sub. 2 (produced byFunakoshi & Co.) being employed as control reference.

Each group of test animals used consisted of 8 to 10 male rats of theCrj: Wistar strain, weighing 180 to 230 g. Test animals were fasted for24 hours before the oral administration of the test samples; in the caseof development of confinement-stress induced ulcers through immersion inwater, 10 minutes after oral administration of the test specimens, theanimals were confined in a stress cage developed by Univ. of Tokyo, thenimmersed up to the ensiform process of sternum in water at 23° C. for 4hours and sacrificed; in the case of formation of indomethacin-inducedulcers, shortly after the materials were given, animals were givenindomethacin orally at a dose of 10 mg/kg and sacrificed after 5 hours.

The stomacks were taken out, followed by fixation with 1% formalin, andincised along the greater curvature to carry our investigation under anilluminated magnifier for ulceration. The degree and extent of lesionand ulcer were rated based on the ulceration index being classified intothe following five numerical categories:

0: normal, with no lesion detected;

1: bleeding or erosion of mucosa;

2: development of less than 5 small ulcers (not greater than 2 mm indiameter);

3: generation of not less than 5 small ulcers or a large ulcer (not lessthan 2 =in diameter);

4: generation of not less than 2 large ulcers.

On the basis of the criteria that the rats with the ulceration index ofnot less than, "2", the ulcer inhibition rate (ED₅₀ ) was calculatedfrom ulcer-generation ratio in the control and the ratio in the testspecimens.

The results are shown in Table 1 (confinement-stress induced ulcersthrough immersion in water) and Table 2 (indomethacin-induced ulcers).

                  TABLE-1                                                         ______________________________________                                        (Hydrorestraint Stress Ulcer Preventing Effect)                                                                 Inhibi-                                                     Animal   Ulcer    tion                                        Material                                                                             Dosage   used (no.                                                                              index    factor                                                                              ED.sub.50                             tested (mg/kg)  of heads)                                                                              (aver. ± SE)                                                                        (%)   (mg/kg)                               ______________________________________                                        Control                                                                              --       10       3.0 ± 0.2                                                                           --    --                                     (1)   20       8        2.5 ± 0.3                                                                           6.3   >20                                    (2)   15       8        0.5 ± 0.3                                                                           87.5  4.0                                          5        8        1.4 ± 0.4                                                                           58.3                                         (3)   10       8        0.3 ± 0.1                                                                           100.0                                              3        8        1.1 ± 0.3                                                                           86.1  1.5                                          1        8        2.1 ± 0.4                                                                           25.0                                         (4)   5        8        1.6 ± 0.3                                                                           44.4  7.0                                          1        8        2.1 ± 0.4                                                                           16.7                                         (5)   5        8        1.5 ± 0.3                                                                           44.0  6.5                                          1        8        2.2 ± 0.4                                                                           14.3                                         (6)   10       8        1.4 ± 0.2                                                                           72.2  5.5                                          3        8        2.4 ± 0.3                                                                           28.0                                         (7)   10       8        1.1 ± 0.2                                                                           75.0  4.5                                          3        8        1.9 ± 0.3                                                                           37.5                                         (8)   1        10       1.5 ± 62.5  0.60                                         0.3      10       2.0 ± 0.3                                                                           30.6                                         (9)   1        10       1.5 ± 0.3                                                                           75.0  0.45                                         0.3      10       1.9 ± 0.2                                                                           37.5                                        (10)   3        10       0.9 ± 0.4                                                                           78.4  1.5                                          1        10       2.0 ± 0.4                                                                           25.5                                        (11)   10       10       1.1 ± 0.2                                                                           85.7                                               3        10       1.4 ± 0.2                                                                           57.1  2.4                                          1        10       2.0 ± 0.4                                                                           25.0                                        (12)   10       10       1.1 ± 0.2                                                                           75.3  6.2                                          3        10       2.6 ± 0.3                                                                           13.6                                        (13)   10       8        1.5 ± 0.4                                                                           50.0  10                                           3        8        2.6 ± 0.3                                                                           13.2                                        (14)   1        10       1.3 ± 0.2                                                                           77.8                                               0.3      10       1.7 ± 0.3                                                                           44.4  0.35                                         0.1      10       1.9 ± 0.4                                                                           22.2                                        (15)   6        10       0.8 ± 0.3                                                                           79.9  3.5                                          3        10       1.8 ± 0.3                                                                           37.5                                        (16)   1        10       1.7 ± 0.3                                                                           44.4  2.0                                          0.3      10       2.5 ± 0.3                                                                           0                                           (17)   0.1      10       0.5 ± 0.2                                                                           95.7                                               0.03     10       1.5 ± 0.3                                                                           81.4  0.005                                        0.01     10       1.7 ± 0.2                                                                           67.1                                               0.003    10       2.2 ± 0.4                                                                           39.0                                        (18)   0.3      10       0.5 ± 0.2                                                                           95.9                                               0.1      10       0.7 ± 0.2                                                                           89.0  0.03                                         0.03     10       1.7 ± 0.3                                                                           49.3                                        (19)   0.3      10       1.1 ± 0.2                                                                           83.3                                               0.1      10       1.6 ± 0.3                                                                           63.0  0.06                                         0.03     10       2.5 ± 0.4                                                                           33.3                                        (20)   3        10       0.9 ± 0.2                                                                           87.7                                               1        10       1.7 ± 0.2                                                                           58.3  0.80                                         0.3      10       2.4 ± 0.3                                                                           22.2                                        (21)   3        10       0.9 ± 0.2                                                                           87.5  0.80                                         1        10       1.6 ± 0.3                                                                           52.4                                        (22)   3        10       1.2 ± 0.3                                                                           70.0  1.8                                          1        10       2.0 ± 0.4                                                                           30.0                                        (23)   3        10       2.0 ± 0.2                                                                           50.0  3.0                                          1        10       2.9 ± 0.3                                                                           12.5                                        (24)   10       10       1.4 ± 0.2                                                                           87.1  2.0                                          3        10       1.7 ± 0.2                                                                           61.4                                        (25)   10       8        1.4 ± 0.2                                                                           62.5  8.0                                          3        8        2.3 ± 0.4                                                                           12.5                                        (26)   10       8        1.1 ± 0.2                                                                           72.2  4.0                                          3        8        1.6 ± 0.3                                                                           44.4                                        (27)   6        8        1.6 ± 0.2                                                                           56.0  5.0                                          3        8        2.1 ± 0.3                                                                           31.8                                        (28)   6        8        1.3 ± 0.3                                                                           70.2  4.0                                          3        8        1.9 ± 0.2                                                                           36.0                                        (29)   6        10       2.0 ± 0.4                                                                           42.2  >6                                           3        10       2.5 ± 0.3                                                                           30.0                                        (30)   6        8        1.1 ± 0.2                                                                           57.8  5.0                                          3        8        2.3 ± 0.4                                                                           29.7                                        (31)   0.3      10       1.0 ± 0.2                                                                           75.0                                               0.1      10       2.2 ± 0.3                                                                           37.5  0.14                                         0.03     10       2.6 ± 0.4                                                                           12.5                                        (32)   1        10       0.8 ± 0.2                                                                           82.3                                               0.3      10       1.5 ± 0.3                                                                           57.0  0.2                                          0.1      10       2.0 ± 0.4                                                                           27.9                                        (33)   5        10       1.2 ± 0.3                                                                           55.0  3.9                                          1        10       2.6 ± 0.3                                                                           25.0                                        (34)   10       10       0.8 ± 0.3                                                                           90.0                                               3        10       1.4 ± 0.4                                                                           60.0  1.3                                          1        10       2.0 ± 0.4                                                                           40.0                                        (35)   3        10       1.2 ± 0.3                                                                           77.5                                               1        10       1.5 ± 0.3                                                                           55.0  0.9                                          0.3      10       2.3 ± 0.3                                                                           21.3                                        (36)   1        10       1.5 ± 0.3                                                                           57.0  0.8                                          0.3      10       2.4 ± 0.4                                                                           22.6                                        (37)   6        10       1.0 ± 0.2                                                                           79.7                                               3        10       1.9 ± 0.2                                                                           45.9  3.0                                          1        10       2.7 ± 8.14                                        (38)   3        10       1.0 ± 0.2                                                                           79.7                                               1        10       1.9 ± 0.2                                                                           45.9  1.5                                          0.3      10       2.7 ± 0.4                                                                           8.1                                         (39)   3        10       0.7 ± 0.2                                                                           85.3                                               1        10       1.0 ± 0.2                                                                           77.5  0.4                                          0.3      10       2.0 ± 0.3                                                                           30.2                                        ______________________________________                                    

                  TABLE-2                                                         ______________________________________                                        (Indomethacin Ulcer Preventing Effect)                                                                          Inhibi-                                                     Animal   Ulcer    tion                                        Material                                                                             Dosage   used (no.                                                                              index    factor                                                                              ED.sub.50                             tested (mg/kg)  of heads)                                                                              (aver. ± SE)                                                                        (%)   (mg/kg)                               ______________________________________                                        Control                                                                              --       10       2.5 ± 0.3                                                                           --    --                                     (1)   20       8        2.4 ± 0.4                                                                           4.0   >20                                    (2)   20       9        0.4 ± 0.2                                                                           100.0                                              6        8        1.4 ± 0.3                                                                           50.0  6.0                                          3        8        1.9 ± 0.4                                                                           30.0                                         (3)   10       9        1.0 ± 0.3                                                                           71.4  4.4                                          3        9        1.7 ± 0.4                                                                           42.9                                         (8)   3        10       1.7 ± 0.3                                                                           42.9  3.8                                          1        10       2.3 ± 0.4                                                                           14.3                                         (9)   3        10       1.5 ± 0.3                                                                           50.5  3.0                                          1        10       2.1 ± 0.3                                                                           37.5                                        (11)   10       10       2.0 ± 0.2                                                                           50.0  10.0                                         3        10       2.6 ± 0.3                                                                           0                                           (12)   10       10       0.8 ± 0.2                                                                           71.4  7.4                                          3        10       1.6 ± 0.3                                                                           48.0                                        (14)   3        10       0.6 ± 0.1                                                                           80.0  1.5                                          1        10       2.0 ± 0.3                                                                           32.0                                        (16)   10       10       1.0 ± 0.2                                                                           60.0  8.2                                          3        10       2.3 ± 0.3                                                                           10.0                                        (18)   1        10        0.2 ± 0.02                                                                         100.0                                              0.3      10       1.4 ± 0.1                                                                           62.5  0.17                                         0.1      10       1.8 ± 0.2                                                                           38.3                                        (19)   10       10       0.4 ± 0.1                                                                           85.7  3.6                                          3        10       1.9 ± 0.2                                                                           42.9                                        (20)   10       10       0.6 ± 0.1                                                                           87.5  3.5                                          3        10       1.3 ± 0.2                                                                           44.4                                        (21)   10       10       1.5 ± 0.3                                                                           80.0  6.0                                          3        10       2.5 ± 0.4                                                                           0                                           (23)   10       10       1.5 ± 0.3                                                                           50.0  10.0                                         3        10       2.0 ± 0.3                                                                           25.0                                        (30)   10       10       0.6 ± 0.1                                                                           71.5                                               3        10       2.1 ± 0.4                                                                           24.0  0.9                                          1        10       2.4 ± 0.5                                                                           10.0                                        (33)   10       10       1.6 ± 0.2                                                                           62.0  6.3                                          3        10       2.3 ± 0.3                                                                           30.0                                        (34)   10       10       1.9 ± 0.2                                                                           70.0  6.0                                          3        10       2.2 ± 0.4                                                                           20.0                                        (35)   10       10       1.0 ± 0.2                                                                           72.5  4.8                                          3        10       2.3 ± 0.4                                                                           29.3                                        ______________________________________                                    

Materials tested in Table 1 is shown hereinafter:

(1) 13, 14-dihydro-15-keto-PGE₂,

(2) 13, 14-dihydro-15-keto-PGE₂ methyl ester,

(3) 13, 14-dihydro-15-keto-PGE₂ ethyl ester,

(4) 13, 14-dihydro-15-keto-PGE₂ -n-propyl ester,

(5) 13, 14-dihydro-15-keto-PGE₂ isopropyl ester,

(6) 13, 14-dihydro-15-keto-PGE₁ methyl ester,

(7) 13, 14-dihydro-15-keto-PGE₁ ethyle ester,

(8) 13, 14-dihydro-6,15-diketo-PGE₁ methyl ester,

(9) 13, 14-dihydro-6,15-diketo-PGE₁ ethyl ester,

(10) 13, 14-dihydro-6,15-diketo-PGE₁ n-butyl ester,

(11) (±)13, 14-dihydro-6,15-diketo-PGE₁ ethyl ester,

(12) 13, 14-dihydro-15-keto-3R,S-methyl-PGE₂ methyl ester,

(13) 13, 14-dihydro-15-keto-3R,S-methyl-PGE₂ ethyl ester,

(14) 13, 14-dihydro-15-keto-16R,S-fluoro-11-dehydroxy-11R-methyl-PGE₂ethyl ester,

(15) 13, 14-dihydro-15-keto-11-dehydroxy-11R-methyl-PGE₂ ethyl ester,

(16) 13, 14-dihydro-15-keto-16R,S-hydroxy-PGE₂ ethyl ester,

(17) 13, 14-dihydro-15-keto-16R,S-fluoro-PGE₂,

(18) 13, 14-dihydro-15-keto-16R,S-fluoro-PGE₂ methyl ester,

(19) 13, 14-dihydro-15-keto-16 R,S-fluoro-PGE₂ ethyl ester,

(20) 13, 14-dihydro-15-keto-16R,S-methyl-PGE₂ methyl ester,

(21) 13, 14-dihydro-15-keto-16R,S-methyl-PGE₂ ethyl ester,

(22) 13, 14-dihydro-15-keto-3R,S,16R,S-dimethyl-PGE₂ methyl ester,

(23) 13, 14-dihydro-15-keto-19-methyl-PGE₂ methyl ester,

(24) 13, 14-dihydro-15-keto-19-methyl-PGE₂ ethyl ester,

(25) 13, 14-dihydro-15-keto-20-isopropylidene-PGE₂ methyl ester,

(26) 13, 14-dihydro-15-keto-20-ethyl-PGE₂ methyl ester,

(27) 13, 14-dihydro-15-keto-20-ethyl-PGE₂ ethyl ester,

(28) 13, 14-dihydro-15-keto-20-ethyl-11-dehydroxy-11R-methyl-PGE₂ methylester,

(29) 13, 14-dihydro-15-keto-20-n-propyl-PGE₂ methyl ester,

(30) 13, 14-dihydro-15-keto-20-ethyl-PGE₁ methyl ester,

(31) 13, 14-dihydro-6,15-diketo-16R,S-fluoro-PGE₁ ethyl ester,

(32) 13,14-dihydro-6,15-diketo-16R,S-fluoro-11-dehydroxy-11R-methyl-PGE₁ ethylester,

(33) 13, 14-dihydro-6,15-diketo-16R,S-methyl-PGE₁ methyl ester,

(34) 13, 14-dihydro-6,15-diketo-16R,S-methyl-PGE₁ ethyl ester,

(35) 13, 14-dihydro-6,15-diketo-19-methyl-PGE₁ methyl ester,

(36) 13, 14-dihydro-6, 15-diketo-19-methyl-PGE₁ ethyl ester,

(37) 13, 14-dihydro-6, 15-diketo-20-methyl-PGE₁ ethyl ester,

(38) 13, 14-dihydro-6, 15-diketo-11-dehydroxy-11R-methyl-PGE₁ methylester,

(39) 13,14-dihydro-6,15-diketo-11-dehydroxy-11R-methyl-PGE₁ ethyl ester.

From the foregoing results, it can be seen that while 13,14-dihydro-15-keto-PGE₂, as a physiologically and pharmacologicallyinactive metabolite, shows no antiulcerative effect, it can haveantiulcerative effect if it is made into an ester compound of 13,14-dihydro-15-keto-PGE or a compound similar thereto.

TEST EXAMPLE 2

The following 4 materials were measured as to their respctive effects ofulcer prevention, intestinal constriction, tracheorelaxation, anduteroconstriction, and examined in comparison to one another. Theresults are shown in Table 3.

                  TABLE-3                                                         ______________________________________                                               Ulcer inhibiting                                                                          Intestinal                                                                              Trachael                                                                              Uterus                                   Material                                                                             effect      constriction                                                                            relaxation                                                                            constriction                             tested ED.sub.50 (mg/kg)                                                                         effect    effect  effect                                   ______________________________________                                        A      0.5         +         +       +                                        B      0.4         +         +       ±                                     C      >20         -         ±    ±                                     D      1.5         -         -       -                                        ______________________________________                                    

Materials tested:

A: PGE₂ (product of Funakoshi Yakuhin K.K.)

B: PGE₂ ethyl ester (produced by Applicant Co.)

C: 13, 14-dihydro-15-keto-PGE₂ (product of Funakoshi Yakuhin K.K.)

D: 13, 14-dihydro-15-keto-PGE₂ ethylester

(1) Antiulcerative Effect

The procedure of Test Example 1 was followed in determining values forhydrorestraint stress-ulcer preventing effect in terms of ED₅₀.

++: alvin flux developed at a concentration lower than 1 mg/kg;

+: alvin flux developed at concentrations of 1˜10 mg/kg;

-: no flux developed at a concentration higher than 10 mg/kg.

(2) Intestinal Constriction Effect

A male Wister rat (of 250˜300 g in weight) was struck to death, andimmediately its carotid artery was cut to dehematize. An ileum portionlocated about 10 cm from the cecum was extracted, and after its contentswere washed away with a Tyrode liquid, a 1.5˜2 cm long part of it wascut off and hung in a Magnus tube.

The constriction of the ileum was brought to rest for 15˜20 minutesuntil the ileum was allowed to be stabilized, and subsequently the ileumwas constricted with 10⁻⁶ g/ml of acetylcholine. After constrictions ofsame magnitude were had two times, the material to be tested wascumulatively administered at one-minute intervals.

Constrictions with the material tested were expressed in terms ofratios, based on constriction per 10⁻⁶ g/ml of acetylcholine, and valuesfor ED₅₀ were determined.

+: ED₅₀ <10⁻⁶ M

±: 10⁻⁴ M≦ED₅₀ ≦10⁻⁶ M

-: 10⁻⁴ M<ED₅₀

(3) Tracheal Relaxation

A male gunea pig (of about 300 g in weight) was struck to death, and itsartery was cut to dehematize. Its trachea, after having been extracted,was cut open lengthwise on the opposite side to the trachea smoothmuscle, and seven tracheal rings were connected by string in achain-like pattern, same being hung in a Magnus tube.

Trachea was brought to rest for 60˜90 minutes and until trachealequilibrium was reached. Thereafter, 5.4×10⁻⁴ M of histamine wasadministered in such manner that it was cumulatively administered at 6minutes' intervals after a constriction peak was reached. Trachealrelaxation with the material tested was expressed in terms of ratio ofconstrictional inhibition under histamine administering, and values forIC₅₀ were determined.

+: IC₅₀ <10⁻⁷ M

±: 10⁻⁵ M≦IC₅₀ ≦10⁻⁷ M

-: 10⁻⁵ M<IC₅₀

(4) Uterine Constriction

A female rat (of 150 g in weight) was dehematized to death, and itsuterus was taken out, which was cut to a length of 1.5-2.5 cm. The cututerus was hung in a magnus tube. The uterus was constricted severaltimes with 1 mU Oxytocin. After stable uterine movement was obtained,the material to be tested was independently administered. Constrictionswith the material were expressed in terms of ratios based onconstriction by 1 mU of oxytocin=100, and values for EC₅₀ weredetermined on the following standards.

+: EC₅₀ <10⁻⁷ M

±: 10⁻⁵ M≦EC₅₀ ≦10⁻⁷ M

-: 10⁻⁵ M<EC₅₀

From the results of the foregoing tests it can be seen that PGE₂ andPGE₂ ethylester can, in addition to their ulcer inhibiting effects,concurrently produce intestinal constriction, tracheal relaxation, anduterus constriction. Whilst, no pharmacological or physiological effect,such as ulcer inhibiting effect, can be found with13,14-dihydro-15-keto-PGE₂. However, it can be recognized that13,14-dihydro-15-keto-PGE₂ ethylester, an ester compound of said 13,14-dihydro-15-keto-PGE₂, can produce a high degree of ulcer inhibitingeffect, though it has no such effet as intestinal, uterus constriction,tracheal relaxation and the like. ##STR46##

What is claimed is:
 1. Prostaglandins E represented by a generalformula:in which X represents: ##STR47## R₁ represents: a hydrogen atom,a physiologically acceptable sat residue, or an ester residue selectedfrom the group consisting of alkyl, benzyl, hydroxyalkyl, alkoxyalkyl,alkylsilyl and tetrahydropyranyl group; R₂ represents: a hydrogen atomor a methyl group; R₃ represents: a hydroxyl or hydroxymethyl group; R₄and R₅ each represents: a hydrogen atom, a methyl group or a halogenatom provided that at least one of R4 and R5 is a halogen atom; and R₆represents: a C₁ -C₉ alkyl group which may have a branch or a doublebond, or a C₁ -C₉ alkyl group having an alkoxy substituent group, the C₂-C₃ bond being a single or double bond.
 2. Prostaglandins E as describedin claim 1, wherein R₄ and R₅ are halogen atoms.
 3. Prostaglandins E asdescribed in claim 1, wherein R₄ and/or R₅ is a fluorine atom. 4.Prostaglandins E as described in claim 1, wherein R₄ or R₅ is a methylgroup.
 5. Prostaglandins E as described in claim 1, which is13,14-dihydro-15-keto-PGE having one or more fluorine atom(s) on16-position or alkyl ester thereof.
 6. Prostaglandins E as described inclaim 1, being 13,14-dihydro-6,15-diketo-16R,S-fluoro-PGE₁ or alkylester thereof.
 7. An anti-ulcer composition comprising an anti-ulcereffective amount of a prostaglandin E expressed by a general formula:##STR48## in which X represents: ##STR49## R₁ represents: a hydrogenatom, a physiologically acceptable sat residue, or an ester residueselected from the group consisting of alkyl, benzyl, hydroxyalkyl,alkoxyalkyl, alkylsilyl and tetrahydropyranyl group;R₂ represents: ahydrogen atom or a methyl group; R₃ represents: a hydroxyl orhydroxymethyl group; R₄ and R₅ each represents: a hydrogen atom, amethyl group or a halogen atom provided that at least one of R₄ and R₅is a halogen atom; and R₆ represents: a C₁ -C₉ alkyl group which mayhave a branch or a double bond, or a C₁ -C₉ alkyl group having an alkoxysubstituent group, the C₂ -C₃ bond being a single or double bond.
 8. Ananti-ulcer composition as in claim 7, wherein R₄ and R₅ are halogenatoms.
 9. An anti-ulcer composition as in claim 7, wherein R₄ and/or R₅is a fluorine atom.
 10. An anti-ulcer composition as in claim 7, whereinR₄ or R₅ is a methyl group.
 11. An anti-ulcer composition as in claim 7,wherein the prostaglandin E is 13,14-dihydro-15-PGE having one or morefluorine atom(s) on 16-position or alkyl ester thereof.
 12. Ananti-ulcer composition as in claim 7, wherein the prostaglandin E is13,14-dihydro-6,15-diketo-16R,S-fluoro-PGE₁ or alkyl ester thereof. 13.A treatment of ulcer by administering an anti-ulcer treating effectiveamount of prostaglandin E to a patient, wherein the prostaglandin E isrepresented by a formula: ##STR50## in which X represents: ##STR51## R₁represents: a hydrogen atom, a physiologically acceptable salt residue,or an ester residue selected from the group consisting of alkyl, benzyl,hydroxyalkyl, alkoxyalkyl, alkylsilyl and tetrahydropyranyl group;R₂represents: a hydrogen atom or a methyl group; R₃ represents: a hydroxylor hydroxymethyl group; R₄ and R₅ each represents: a hydrogen atom, amethyl group or a halogen atom provided that at least one of R₄ and R₅is a halogen atom; and R₆ represents: a C₁ -C₉ alkyl group which mayhave a branch or a double bond, or a C₁ -C₉ alkyl group having an alkoxysubstituent group, the C₂ -C₃ bond being a single or double bond.